PUBMED20130502ctdBCIVLearningDataSet.key20921890title0An open-label tolerability study of BL-1020 antipsychotic: a novel gamma aminobutyric acid ester of perphenazine.abstract114BACKGROUND: BL-1020, a novel gamma aminobutyric acid (GABA) ester of perphenazine, is a new oral antipsychotic with a strong affinity for dopamine and serotonin receptors. Unlike first- and second-generation antipsychotics, it has agonist activity at GABA(A).
OBJECTIVE: This is the first study to examine tolerability and safety of BL-1020 in schizophrenia.
METHODS: This was a phase-II, open-label, multicenter, 6-week study treating patients (n = 36) with chronic schizophrenia. Dosing started at 20 mg/d and increased over 7 days to 40 mg/d. Weekly assessments were conducted.
RESULTS: All but 1 patient was titrated to 30 mg/d at day 4; on day 7, 30 were titrated to 40 mg/d. Four patients discontinued the study prematurely. There was no clinically relevant increase in vital signs, sedation, dizziness, or other central nervous system effects or electrocardiogram or laboratory abnormalities and a small increase in weight. Ten patients experienced extrapyramidal symptoms (EPS) requiring treatment with an anticholinergic; 4 patients were unable to reach maximum dose because of EPS. Extrapyramidal Symptom Rating Scale did not indicate clinically significant changes in EPS. The most common adverse event was insomnia (6 patients); other frequent adverse effects (all n = 3) were extrapyramidal disorder, headache, parkinsonism, tremor, and hyperprolactinemia. There was improvement on Positive and Negative Syndrome Scale and Clinical Global Impression of Change with 22 patients showing at least 20% decrease by end point on Positive and Negative Syndrome Scale and 31 patients showing at least minimal improvement on Clinical Global Impression of Change.
CONCLUSIONS: These data suggest that 20 to 40 mg/d of BL-1020 is associated with clinically relevant improvement of psychosis with no worsening of EPS and support further testing in randomized controlled trials.chemCHOLINERGIC ANTAGONISTSchemPERPHENAZINE GABA ESTERdiseaseSLEEP INITIATION AND MAINTENANCE DISORDERSdiseaseHYPERPROLACTINEMIAdiseaseBASAL GANGLIA DISEASESdiseaseSCHIZOPHRENIAdiseaseTREMORdiseasePARKINSON DISEASE, SECONDARYdiseaseHEADACHEgenePRLaction termexpressionixnperphenazine GABA ester plays a role in or acts as a marker for Basal Ganglia Diseasesixnperphenazine GABA ester plays a role in or acts as a marker for Parkinson Disease, Secondaryixnperphenazine GABA ester plays a role in or acts as a marker for Headacheixnperphenazine GABA ester results in increased expression of PRL proteinixnperphenazine GABA ester plays a role in or acts as a marker for Sleep Initiation and Maintenance Disordersixnperphenazine GABA ester plays a role in or acts as a marker for HyperprolactinemiaixnCholinergic Antagonists has a real or putative therapeutic role towards Basal Ganglia Diseasesixnperphenazine GABA ester plays a role in or acts as a marker for Tremorixnperphenazine GABA ester has a real or putative therapeutic role towards Schizophrenia15684285title0Effect of rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 on bleomycin-induced lung injury.abstract99Thiazolidinedione rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), are two peroxisome proliferator-activated receptor (PPAR)-gamma ligands. The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ2 on the lung injury caused by bleomycin administration. Mice subjected to intratracheal administration of bleomycin developed significant lung injury. An increase in immunoreactivity to nitrotyrosine, poly(ADP ribose) polymerase (PARP) and inducible nitric oxide synthase as well as a significant loss of body weight and mortality was observed in the lung of bleomycin-treated mice. Administration of the two PPAR-gamma agonists rosiglitazone (10 mg x kg(-1) i.p.) and 15d-PGJ2 (30 microg x kg(-1) i.p.) significantly reduced the: 1) loss of body weight, 2) mortality rate, 3) infiltration of the lung with polymorphonuclear neutrophils (myeloperoxidase activity), 4) oedema formation, and 5) histological evidence of lung injury. Administration of rosiglitazone and 15d-PGJ2 also markedly reduced the nitrotyrosine, PARP and inducible nitric oxide synthase formation. In addition, treatment with the PPAR-gamma antagonist bisphenol A diglycidyl ether (1 mg x kg(-1) i.p. 30 min before the rosiglitazone or 15d-PGJ2) significantly antagonised the effect of the two PPAR-gamma agonists. These results demonstrate that the two peroxisome proliferator-activated receptor-gamma agonists, rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, significantly reduce lung injury induced by bleomycin in mice.chemROSIGLITAZONEchem2,2-BIS(4-GLYCIDYLOXYPHENYL)PROPANEchemBLEOMYCINchem15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J2diseasePULMONARY EDEMAdiseaseLUNG INJURYgeneNOS2genePPARGaction termreactionaction termexpressionaction termbindingaction termactivityixnBleomycin results in increased expression of NOS2 proteinixnBleomycin plays a role in or acts as a marker for Lung Injuryixn15-deoxy-delta(12,14)-prostaglandin J2 inhibits the reaction [Bleomycin results in increased expression of NOS2 protein]ixn15-deoxy-delta(12,14)-prostaglandin J2 has a real or putative therapeutic role towards Lung Injuryixnrosiglitazone inhibits the reaction [Bleomycin results in increased expression of NOS2 protein]ixn15-deoxy-delta(12,14)-prostaglandin J2 has a real or putative therapeutic role towards Pulmonary Edemaixnrosiglitazone has a real or putative therapeutic role towards Lung Injuryixn2,2-bis(4-glycidyloxyphenyl)propane binds to and results in decreased activity of PPARG proteinixnBleomycin plays a role in or acts as a marker for Pulmonary Edemaixnrosiglitazone has a real or putative therapeutic role towards Pulmonary Edema20133848title0Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression.abstract95As the result of genetic alterations and tumor hypoxia, many cancer cells avidly take up glucose and generate lactate through lactate dehydrogenase A (LDHA), which is encoded by a target gene of c-Myc and hypoxia-inducible factor (HIF-1). Previous studies with reduction of LDHA expression indicate that LDHA is involved in tumor initiation, but its role in tumor maintenance and progression has not been established. Furthermore, how reduction of LDHA expression by interference or antisense RNA inhibits tumorigenesis is not well understood. Here, we report that reduction of LDHA by siRNA or its inhibition by a small-molecule inhibitor (FX11 [3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid]) reduced ATP levels and induced significant oxidative stress and cell death that could be partially reversed by the antioxidant N-acetylcysteine. Furthermore, we document that FX11 inhibited the progression of sizable human lymphoma and pancreatic cancer xenografts. When used in combination with the NAD(+) synthesis inhibitor FK866, FX11 induced lymphoma regression. Hence, inhibition of LDHA with FX11 is an achievable and tolerable treatment for LDHA-dependent tumors. Our studies document a therapeutical approach to the Warburg effect and demonstrate that oxidative stress and metabolic phenotyping of cancers are critical aspects of cancer biology to consider for the therapeutical targeting of cancer energy metabolism.chemN-(4-(1-BENZOYLPIPERIDIN-4-YL)BUTYL)-3-(PYRIDIN-3-YL)ACRYLAMIDEchem3-DIHYDROXY-6-METHYL-7-(PHENYLMETHYL)-4-PROPYLNAPHTHALENE-1-CARBOXYLIC ACIDchemDOXYCYCLINEchemGOSSYPOLchemREACTIVE OXYGEN SPECIESdiseasePANCREATIC NEOPLASMSdiseaseLYMPHOMAgeneLDHAgeneNAMPTgeneMYCaction termexpressionaction termbindingaction termactivityaction termabundanceixn[3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid binds to and results in decreased activity of LDHA protein] which results in increased abundance of Reactive Oxygen Speciesixn[N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide binds to and results in decreased activity of NAMPT protein] which results in increased abundance of Reactive Oxygen Speciesixn3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid has a real or putative therapeutic role towards LymphomaixnDoxycycline has a real or putative therapeutic role towards Lymphomaixn3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid has a real or putative therapeutic role towards Pancreatic Neoplasmsixn3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid binds to and results in decreased activity of LDHA proteinixnN-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide results in decreased activity of NAMPT proteinixnGossypol results in decreased activity of LDHA proteinixnDoxycycline results in decreased expression of MYCixn3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid does not affect the expression of MYC protein20659490title0Inflammatory effects of inhaled sulfur mustard in rat lung.abstract60Inhalation of sulfur mustard (SM), a bifunctional alkylating agent that causes severe lung damage, is a significant threat to both military and civilian populations. The mechanisms mediating its cytotoxic effects are unknown and were investigated in the present studies. Male rats Crl:CD(SD) were anesthetized, and then intratracheally intubated and exposed to 0.7-1.4mg/kg SM by vapor inhalation. Animals were euthanized 6, 24, 48h or 7days post-exposure and bronchoalveolar lavage fluid (BAL) and lung tissue collected. Exposure of rats to SM resulted in rapid pulmonary toxicity, including focal ulceration and detachment of the trachea and bronchial epithelia from underlying mucosa, thickening of alveolar septal walls and increased numbers of inflammatory cells in the tissue. There was also evidence of autophagy and apoptosis in the tissue. This was correlated with increased BAL protein content, a marker of injury to the alveolar epithelial lining. SM exposure also resulted in increased expression of markers of inflammation including cyclooxygenase-2 (COX-2), tumor necrosis factor- (TNF ), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-9 (MMP-9), each of which has been implicated in pulmonary toxicity. Whereas COX-2, TNF and iNOS were mainly localized in alveolar regions, MMP-9 was prominent in bronchial epithelium. In contrast, expression of the anti-oxidant hemeoxygenase, and the anti-inflammatory collectin, surfactant protein-D, decreased in the lung after SM exposure. These data demonstrate that SM-induced oxidative stress and injury are associated with the generation of cytotoxic inflammatory proteins which may contribute to the pathogenic response to this vesicant.chemMUSTARD GASdiseaseLUNG INJURYgeneHMOX1genePARP1genePTGS2geneCASP3geneTNFgeneNOS2geneCASP9geneSFTPDgeneMMP9action termexpressionaction termcleavageixnMustard Gas plays a role in or acts as a marker for Lung InjuryixnMustard Gas results in increased expression of NOS2 proteinixnMustard Gas results in increased expression of MMP9 proteinixnMustard Gas results in increased expression of PTGS2 proteinixnMustard Gas results in increased expression of HMOX1 proteinixnMustard Gas results in increased expression of TNF proteinixnMustard Gas results in decreased expression of SFTPD proteinixnMustard Gas results in increased cleavage of CASP3 proteinixnMustard Gas results in increased cleavage of CASP9 proteinixnMustard Gas results in increased cleavage of PARP1 protein19028542title0Resveratrol supplementation worsen the dysregulation of genes involved in hepatic lipid homeostasis observed in hyperhomocysteinemic mice.abstract139Hyperhomocysteinemia is characterized by an increase of plasma homocysteine, a thiol-containing amino acid produced during methionine metabolism. Hyperhomocysteinemia has often been associated with coronary artery disease, vascular thrombosis and the development of premature atherosclerosis. We have recently demonstrated that the supplementation of catechin, a polyphenol found in the red wine, significantly reduced plasma homocysteine level in cystathionine beta synthase (CBS) deficient mice, a murine model of hyperhomocysteinemia. In the present study, we have investigated the influence of another well-studied polyphenol found in red wine, resveratrol, on hyperhomocysteinemia. After two months on high methionine diet, heterozygous Cbs deficient mice were administrated the resveratrol in drinking water (0.001%) for one month. High methionine diet significantly increased serum homocysteine levels, and decreased the serum activity of HDL-associated enzyme paraoxonase-1. Chronic administration of resveratrol significantly increased plasma homocysteine level, which was associated with a decreased serum paraoxonase-1 activity, in hyperhomocysteinemic mice. Then we looked at gene expression of several proteins involved in HDL stability and found a down-regulation of lecithin:cholesterol acyltransferase. In conclusion, we found a deleterious effect of resveratrol onto homocysteine and HDL metabolism in a murine model of hyperhomocysteinemia.chemHOMOCYSTEINEchemRESVERATROLchemMETHIONINEdiseaseHYPERHOMOCYSTEINEMIAdiseaseATHEROSCLEROSISdiseaseTHROMBOSISdiseaseCORONARY ARTERY DISEASEgenePON1geneCBSgeneLCATaction termexpressionaction termactivityaction termabundanceixnHomocysteine plays a role in or acts as a marker for Coronary Artery DiseaseixnHomocysteine plays a role in or acts as a marker for ThrombosisixnHomocysteine plays a role in or acts as a marker for AtherosclerosisixnCBS plays a role in or acts as a marker for HyperhomocysteinemiaixnHomocysteine plays a role in or acts as a marker for Hyperhomocysteinemiaixn[Methionine results in increased abundance of Homocysteine] which results in decreased activity of PON1 proteinixn[resveratrol results in increased abundance of Homocysteine] which results in decreased activity of PON1 proteinixnresveratrol plays a role in or acts as a marker for Hyperhomocysteinemiaixnresveratrol results in decreased expression of LCAT mRNAixnPON1 plays a role in or acts as a marker for Hyperhomocysteinemia10617681title0Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine.abstract104Dexfenfluramine was approved in the United States for long-term use as an appetite suppressant until it was reported to be associated with valvular heart disease. The valvular changes (myofibroblast proliferation) are histopathologically indistinguishable from those observed in carcinoid disease or after long-term exposure to 5-hydroxytryptamine (5-HT)(2)-preferring ergot drugs (ergotamine, methysergide). 5-HT(2) receptor stimulation is known to cause fibroblast mitogenesis, which could contribute to this lesion. To elucidate the mechanism of "fen-phen"-associated valvular lesions, we examined the interaction of fenfluramine and its metabolite norfenfluramine with 5-HT(2) receptor subtypes and examined the expression of these receptors in human and porcine heart valves. Fenfluramine binds weakly to 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors. In contrast, norfenfluramine exhibited high affinity for 5-HT(2B) and 5-HT(2C) receptors and more moderate affinity for 5-HT(2A) receptors. In cells expressing recombinant 5-HT(2B) receptors, norfenfluramine potently stimulated the hydrolysis of inositol phosphates, increased intracellular Ca(2+), and activated the mitogen-activated protein kinase cascade, the latter of which has been linked to mitogenic actions of the 5-HT(2B) receptor. The level of 5-HT(2B) and 5-HT(2A) receptor transcripts in heart valves was at least 300-fold higher than the levels of 5-HT(2C) receptor transcript, which were barely detectable. We propose that preferential stimulation of valvular 5-HT(2B) receptors by norfenfluramine, ergot drugs, or 5-HT released from carcinoid tumors (with or without accompanying 5-HT(2A) receptor activation) may contribute to valvular fibroplasia in humans.chemDEXFENFLURAMINEchemMETHYSERGIDEchemNORFENFLURAMINEchemFENFLURAMINEchemERGOTAMINEdiseaseHEART VALVE DISEASESgeneHTR2AgeneHTR2BgeneHTR2Caction termbindingaction termactivityixnDexfenfluramine plays a role in or acts as a marker for Heart Valve DiseasesixnErgotamine plays a role in or acts as a marker for Heart Valve DiseasesixnMethysergide plays a role in or acts as a marker for Heart Valve DiseasesixnFenfluramine binds to HTR2B proteinixnNorfenfluramine binds to and results in increased activity of HTR2B proteinixnFenfluramine binds to HTR2C proteinixnNorfenfluramine binds to HTR2C proteinixnFenfluramine binds to HTR2A proteinixnNorfenfluramine binds to HTR2A proteinixnHTR2B plays a role in or acts as a marker for Heart Valve Diseases19103299title0Docetaxel/zoledronic acid combination triggers apoptosis synergistically through downregulating antiapoptotic Bcl-2 protein level in hormone-refractory prostate cancer cells.abstract175Docetaxel, a semi-synthetic taxane analogue, is used effectively in the treatment of metastatic prostate cancer. Zoledronic acid, the most potent member of bisphosphonates, has shown pleiotropic anti-tumoral effects on prostate cancer cells. We have explored the possible additive/synergistic effects and the apoptotic pathways induced by combination treatment of docetaxel and zoledronic acid in hormone and drug refractory, PC-3 and DU-145 prostate cancer cells. Combination of docetaxel and zoledronic acid synergistically inhibits cell growth in PC-3 and DU-145 cells. Moreover, this effect was due to downregulation of antiapoptotic protein Bcl-2 in PC-3 and DU-145 cells. In conclusion, docetaxel/zoledronic acid combination is potentially a novel and effective approach for the treatment of prostate cancer.chemDOCETAXELchemZOLEDRONIC ACIDdiseasePROSTATIC NEOPLASMSgeneBCL2action termexpressionaction termcotreatmentixnzoledronic acid has a real or putative therapeutic role towards Prostatic Neoplasmsixndocetaxel has a real or putative therapeutic role towards Prostatic Neoplasmsixn[zoledronic acid co-treated with docetaxel] results in decreased expression of BCL2 protein21281732title0Imbalanced dietary ascorbic acid alters molecular pathways involved in skeletogenesis of developing European sea bass (Dicentrarchus labrax).abstract142The influence of dietary ascorbic acid (AA) on growth and morphogenesis during the larval development of European sea bass (Dicentrarchus labrax) was evaluated until 45days post hatching. Diets incorporated 0, 5, 15, 30, 50 or 400mg AA per kg diet to give AA-0, AA-5, AA-15, AA-30, AA-50 and AA-400 dietary treatments, respectively. Dietary AA levels lower than 15mg/kg reduced larval growth and survival was affected in specimens fed diets devoid of AA. Globally, disruption of the expression of genes involved in AA and calcium absorption in the intestine (SVCT-1, TRPV-6), skeletogenesis (BMP-4, IGF-1, RAR ) and bone mineralization (VDR , osteocalcin) were observed in groups fed doses lower and higher than 50mg AA/kg diet. Such disturbances detected at molecular level were associated with disruptions of the ossification process and the appearance of skeletal abnormalities.chemASCORBIC ACIDdiseaseBONE DISEASESgeneVDRBETAgenePPARGgeneBMP4geneGLAgeneSVCT1geneRARGgeneIGF1geneTRPV6action termexpressionixnAscorbic Acid plays a role in or acts as a marker for Bone DiseasesixnAscorbic Acid results in decreased expression of GLA mRNAixnAscorbic Acid results in increased expression of SVCT1 mRNAixnAscorbic Acid results in decreased expression of TRPV6 mRNAixnAscorbic Acid results in decreased expression of RARG mRNAixnAscorbic Acid affects the expression of BMP4 mRNAixnAscorbic Acid affects the expression of PPARG mRNAixnAscorbic Acid results in decreased expression of VDRBETA mRNAixnAscorbic Acid affects the expression of IGF1 mRNA12503773title0Effects of three H2-receptor antagonists (cimetidine, famotidine, ranitidine) on serum gastrin level.abstract102We investigated the pattern of changes in serum gastrin level produced by three H2-receptor antagonists (H2RA) in patients with gastric and duodenal ulcers between 1990 and 1999. The subjects were 51 patients (cimetidine: 18 patients; famotidine: 16 patients; ranitidine: 17 patients). The gastrin test (in the fasting and meal-stimulated states) was conducted during drug administration and on the fourth day after drug cessation. After cessation of the drug therapy, the fasting serum gastrin level was significantly lower than that during the drug therapy with the three H2RAs. Gastrin level in the fasting test was significantly higher during famotidine therapy than during cimetidine therapy (p = 0.0123). In the meal-stimulated gastrin test, the AUC of gastrin during treatment with H2RA treatment was significantly higher with famotidine than with cimetidine (p = 0.0024). The results indicate different patterns of change in the serum gastrin level in the fasting and meal-stimulated test according to the H2RA administered. Gastrin level was highest in patients administered famotidine and lowest among those administered cimetidine. The pattern of gastrin change in patients administered ranitidine was intermediate between famotidine and cimetidine.chemCIMETIDINEchemRANITIDINEchemFAMOTIDINEdiseaseDUODENAL ULCERdiseaseSTOMACH ULCERgeneGASTaction termexpressionixnCimetidine affects the expression of GAST proteinixnRanitidine affects the expression of GAST proteinixnFamotidine has a real or putative therapeutic role towards Stomach UlcerixnRanitidine has a real or putative therapeutic role towards Stomach UlcerixnCimetidine has a real or putative therapeutic role towards Stomach UlcerixnCimetidine has a real or putative therapeutic role towards Duodenal UlcerixnFamotidine affects the expression of GAST proteinixnFamotidine has a real or putative therapeutic role towards Duodenal UlcerixnRanitidine has a real or putative therapeutic role towards Duodenal Ulcer16935385title0Pravastatin reduces lung metastasis of rat hepatocellular carcinoma via a coordinated decrease of MMP expression and activity.abstract127BACKGROUND/AIMS: Statins have beneficial effects in early pre-clinical models of hepatocellular carcinoma (HCC). Our aim was to test the efficacy of pravastatin on the progression of established HCC in rat, and to study its mechanisms.
METHODS: HCC was induced with diethylnitrosamine and N-nitrosomorpholine. After 14 weeks, all rats developed HCC and then received pravastatin or its solvent for 10 weeks (10 rats/group).
RESULTS: Liver tumor mass was lower in pravastatin group (PG) than control group (CG), as estimated from the number of liver tumors (p<0.004) and the liver weight/body weight ratio (p<0.04). Every CG rat surviving at 24 weeks (4/4) had lung metastasis, against only 5/8 in PG. Moreover, the percentage of lung surface occupied by metastasis was 10-fold smaller in PG than CG (p<0.016). Pravastatin decreased liver matrix metalloproteinase (MMP)-9 activity and mostly suppressed MMP-2 activation (p<0.004), likely because it decreased expression of MMP-14 and tissue inhibitor of matrix metalloproteinases-2 (p<0.01), required for MMP-2 activation.
CONCLUSIONS: Pravastatin reduces progression and limits metastatic diffusion of established HCC. This could be linked to the decreased MMP activity. These results, obtained in a very aggressive HCC model, further suggest the potential benefit of statins in human HCC.chemN-NITROSOMORPHOLINEchemDIETHYLNITROSAMINEchemPRAVASTATINdiseaseCARCINOMA, HEPATOCELLULARgeneTIMP1geneMMP9geneMMP2geneTIMP2geneMMP14action termexpressionaction termactivityixnDiethylnitrosamine plays a role in or acts as a marker for Carcinoma, HepatocellularixnN-nitrosomorpholine plays a role in or acts as a marker for Carcinoma, HepatocellularixnPravastatin results in decreased activity of MMP9 proteinixnPravastatin results in decreased activity of MMP2 proteinixnPravastatin results in decreased expression of MMP9 mRNAixnPravastatin results in decreased expression of MMP2 mRNAixnPravastatin results in decreased expression of MMP14 mRNAixnPravastatin results in decreased expression of TIMP1 mRNAixnPravastatin results in decreased expression of TIMP2 mRNA20823682title0Amelioration of dextran sulfate sodium-induced chronic colitis by sulfasalazine salicylazosulfapyridine via reducing NF-kappaB transcription factor p65 recruitment to ICAM-1 gene promoters.abstract190Sulfasalazine salicylazosulfapyridine (SASP), consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, is an effective drug in the treatment of inflammatory bowel diseases (IBD). However, its mechanism of action remains a matter of debate. The objective of our work was to investigate SASP''s effect on NF-kappaB signal transduction pathway in transcriptional regulation level. Repeated colitis was induced by administration of 4 cycles of 4% dextran sulfate sodium (DSS); The severity of colitis was assessed on the basis of clinical signs, colon length, and histology scores. Moreover, sIgA and haptoglobin (HP) were analyzed by enzyme linked immunosorbent assay, and ICAM-1 gene expression was analyzed by quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR) using SYBA green I. NF-kappaB signal transduction proteins and transcriptional factor p65 interaction with promoter of ICAM-1 were assessed by western blotting and chromatin immunoprecipitation assay. SASP administration significantly attenuated the colitis signs and caused substantial reductions of HP expression, and maintained the level of cecum sIgA. SASP inhibited ICAM-1 gene expression and had no effect on MIF gene expression. Also, SASP was able to reduce p-IkBalpha protein expression; however, no change in the activation of IKKalpha, IKKbeta, p65, and IKBalpha was noted. SASP inhibited p65 recruitment to the gene ICAM-1 promoter. In conclusion, inhibition of NF-kappaB pathway signal proteins and blockade of p65 binding to gene ICAM-1 promoter might explain the effect and mechanisms of SASP at alleviating DSS-induced colitis in mice.chemDEXTRAN SULFATEchemSULFASALAZINEdiseaseCOLITISgeneNFKBIAgeneIKBKBgeneRELAgeneICAM1geneCHUKaction termreactionaction termexpressionaction termbindingaction termactivityixnDextran Sulfate plays a role in or acts as a marker for ColitisixnSulfasalazine inhibits the reaction [RELA protein binds to ICAM1 promoter]ixnSulfasalazine results in decreased expression of ICAM1 mRNAixnSulfasalazine results in decreased expression of NFKBIA proteinixnSulfasalazine does not affect the activity of NFKBIA proteinixnSulfasalazine does not affect the activity of CHUK proteinixnSulfasalazine does not affect the activity of RELA proteinixnSulfasalazine does not affect the activity of IKBKB proteinixnSulfasalazine has a real or putative therapeutic role towards Colitis20338863title0Melatonin inhibits benzene-induced lipid peroxidation in rat liver.abstract68We studied the antioxidative role of melatonin against benzene toxicity in rat liver. The inhibition of mitochondrial and microsomal lipid peroxidation differed between 24-hour (single-dose), 15-day, and 30-day treatments. Inhibition of mitochondrial lipid peroxidation was the highest after the single dose of melatonin, whereas highest microsomal inhibition was recorded after 30 days of melatonin treatment. No significant difference was recorded between 15-day and 30-day treatments. Cytochrome P 4502E1 (CYP 4502E1) activity declined after the single-dose and 15-day melatonin treatment in the benzene-treated group, but it rose again, though not significantly after 30 days of treatment. Liver histopathology generally supported these findings. Phenol concentration in the urine samples declined in melatonin and benzene-treated rats. Our results show that melatonin affects CYP 4502E1, which is responsible for benzene metabolism. Inhibition of its metabolism correlated with lower lipid peroxidation. In conclusion, melatonin was found to be protective against lipid peroxidation induced by benzene.chemMELATONINchemBENZENEdiseaseDRUG-INDUCED LIVER INJURYdiseaseNECROSISgeneCYP2E1action termreactionaction termactivityixnBenzene plays a role in or acts as a marker for NecrosisixnMelatonin has a real or putative therapeutic role towards Drug-Induced Liver InjuryixnMelatonin inhibits the reaction [Benzene results in increased activity of CYP2E1 protein]ixnBenzene plays a role in or acts as a marker for Drug-Induced Liver InjuryixnMelatonin has a real or putative therapeutic role towards NecrosisixnBenzene results in increased activity of CYP2E1 protein19023134title0Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy.abstract112By mimicking sympathetic stimulation in vivo, we previously reported that mice globally lacking serotonin 5-HT(2B) receptors did not develop isoproterenol-induced left ventricular hypertrophy. However, the exact cardiac cell type(s) expressing 5-HT(2B) receptors (cardiomyocytes versus noncardiomyocytes) involved in pathological heart hypertrophy was never addressed in vivo. We report here that mice expressing the 5-HT(2B) receptor solely in cardiomyocytes, like global 5-HT(2B) receptor-null mice, are resistant to isoproterenol-induced cardiac hypertrophy and dysfunction, as well as to isoproterenol-induced increases in cytokine plasma-levels. These data reveal a key role of noncardiomyocytes in isoproterenol-induced hypertrophy in vivo. Interestingly, we show that primary cultures of angiotensinogen null adult cardiac fibroblasts are releasing cytokines on stimulation with either angiotensin II or serotonin, but not in response to isoproterenol stimulation, demonstrating a critical role of angiotensinogen in adrenergic-dependent cytokine production. We then show a functional interdependence between AT(1)Rs and 5-HT(2B) receptors in fibroblasts by revealing a transinhibition mechanism that may involve heterodimeric receptor complexes. Both serotonin- and angiotensin II-dependent cytokine production occur via a Src/heparin-binding epidermal growth factor-dependent transactivation of epidermal growth factor receptors in cardiac fibroblasts, supporting a common signaling pathway. Finally, we demonstrate that 5-HT(2B) receptors are overexpressed in hearts from patients with congestive heart failure, this overexpression being positively correlated with cytokine and norepinephrine plasma levels. Collectively, these results reveal for the first time that interactions between AT(1) and 5-HT(2B) receptors coexpressed by noncardiomyocytes are limiting key events in adrenergic agonist-induced, angiotensin-dependent cardiac hypertrophy. Accordingly, antagonists of 5-HT(2B) receptors might represent novel therapeutics for sympathetic overstimulation-dependent heart failure.chemISOPROTERENOLchemZD 7155diseaseHEART FAILUREdiseaseCARDIOMEGALYgeneIL6geneTNFgeneHTR2BgeneIL1BgeneAGTaction termreactionaction termexpressionixnIsoproterenol plays a role in or acts as a marker for CardiomegalyixnIsoproterenol results in increased expression of TNFixnIsoproterenol results in increased expression of IL1BixnIsoproterenol results in increased expression of AGT proteinixnIsoproterenol results in increased expression of IL6 proteinixnZD 7155 inhibits the reaction [Isoproterenol results in increased expression of IL6 protein]ixnZD 7155 inhibits the reaction [Isoproterenol results in increased expression of IL1B protein]ixnZD 7155 inhibits the reaction [Isoproterenol results in increased expression of TNF protein]ixnHTR2B plays a role in or acts as a marker for CardiomegalyixnHTR2B plays a role in or acts as a marker for Heart Failure19781537title0Synergistic mitosis-arresting effects of arsenic trioxide and paclitaxel on human malignant lymphocytes.abstract105The treatment outcome of acute lymphoblastic leukemia (ALL) has improved steadily over the last 50 years. However, the cure rates are unlikely to be raised further with current therapies. Since increasing the dosage of chemotherapeutic agents could also elevate toxicity, a solution to how one could achieve maximum therapeutic effect with the minimum dosage possible is imminent. One possibility is the employment of combination drug therapies. Arsenic trioxide (ATO) is a widely used drug for acute promyelocytic leukemia (APL). Its combination with other drugs presented therapeutic activities in malignant cancers other than APL. Considering the fact that ATO induces mitotic arrest prior to apoptosis induction, we attempted to investigate the potential anti-cancer effects of ATO in combination with the microtubule-stabilizing agent, paclitaxel (PTX), using malignant lymphocytes as in vitro models. Three malignant lymphocytic cell lines and primary cells were treated with ATO and/or PTX. Using the Chou-Talalay analysis for evaluation of combined effect of ATO and PTX, we found a synergistic effect of the two drugs in the inhibition of cell growth. We also found that the combination of ATO and PTX at low concentrations synergistically induced mitotic arrest followed by apoptosis in malignant lymphocytes, which increased phosphorylated cyclin-dependent kinase 1 (Cdk1) on Thr(161) and promoted the dysregulated activation of Cdk1. The ATO/PTX combination also significantly enhanced the activation of spindle checkpoint by inducing the formation of the inhibitory checkpoint complex BubR1/Cdc20. Our study provided the first in vitro demonstration that low concentrations of ATO and PTX synergistically induce mitotic arrest in malignant lymphocytes.chemARSENIC TRIOXIDEchemPACLITAXELdiseasePRECURSOR CELL LYMPHOBLASTIC LEUKEMIA-LYMPHOMAdiseaseLEUKEMIA, PROMYELOCYTIC, ACUTEgeneCDK1geneCDC27geneCDC20geneBUB1BgeneCDC25Caction termexpressionaction termreactionaction termbindingaction termcotreatmentaction termactivityixnarsenic trioxide has a real or putative therapeutic role towards Precursor Cell Lymphoblastic Leukemia-Lymphomaixn[arsenic trioxide co-treated with Paclitaxel] promotes the reaction [BUB1B protein binds to CDC20 protein]ixn[arsenic trioxide co-treated with Paclitaxel] results in increased activity of CDK1 proteinixn[arsenic trioxide co-treated with Paclitaxel] results in increased expression of BUB1B protein modified formixnarsenic trioxide has a real or putative therapeutic role towards Leukemia, Promyelocytic, Acuteixn[arsenic trioxide co-treated with Paclitaxel] results in increased expression of CDK1 protein modified formixnPaclitaxel has a real or putative therapeutic role towards Precursor Cell Lymphoblastic Leukemia-Lymphomaixn[arsenic trioxide co-treated with Paclitaxel] results in increased expression of CDC25C protein modified formixn[arsenic trioxide co-treated with Paclitaxel] results in increased expression of CDC27 protein modified form18552690title0Metallothionein alleviates glutathione depletion-induced oxidative cardiomyopathy in murine hearts.abstract100OBJECTIVE: Antioxidant therapy has shown some promise in critical care medicine in which glutathione depletion and heart failure are often seen in critically ill patients. This study was designed to examine the impact of glutathione depletion and the free radical scavenger, metallothionein (MT), on cardiac function.
DESIGN: Friend virus B and MT transgenic mice were given the glutathione synthase inhibitor buthionine sulfoximine (buthionine sulfoximine [BSO], 30 mmol/L) in drinking water for 2 wks.
MEASUREMENTS: Echocardiographic and cardiomyocyte functions were evaluated, including myocardial geometry, fraction shortening, peak shortening, time-to-90% relengthening (TR90), maximal velocity of shortening/relengthening (+/-dL/dt), intracellular Ca2+ rise, sarcoplasmic reticulum Ca2+ release, and intracellular Ca2+ decay rate. Sacro (endo)plasmic reticulum Ca2+-ATPase function was evaluated by 45Ca uptake. Highly reactive oxygen species, caspase-3, and aconitase activity were detected by fluorescent probe and colorimetric assays.
MAIN RESULT: BSO elicited lipid peroxidation, protein carbonyl formation, mitochondrial damage, and apoptosis. BSO also reduced wall thickness, enhanced end systolic diameter, depressed fraction shortening, peak shortening, +/-dL/dt, sarcoplasmic reticulum Ca2+ release, 45Ca uptake, and intracellular Ca2+ decay, leading to prolonged TR90. BSO-induced mitochondrial loss and myofilament aberration. MT transgene itself had little effect on myocardial mechanics and ultrastructure. However, it alleviated BSO-induced myocardial functional, morphologic, and carbonyl changes. Western blot analysis showed reduced expression of sacro (endo)plasmic reticulum Ca2+-ATPase2a, Bcl-2 and phosphorylated GSK-3beta, enhanced calreticulin, Bax, p53, myosin heavy chain-beta isozyme switch, and IkappaB phosphorylation in FVB-BSO mice, all of which with the exception of p53 were nullified by MT.
CONCLUSION: Our findings suggest a pathologic role of glutathione depletion in cardiac dysfunction and the therapeutic potential of antioxidants.chemBUTHIONINE SULFOXIMINEchemTOCOPHEROLSdiseaseHEART SEPTAL DEFECTS, VENTRICULARgeneGSSgeneBAXgeneATP2A2geneBCL2geneTRP53geneACO2geneGSK3Baction termexpressionaction termphosphorylationaction termactivityixnButhionine Sulfoximine results in decreased activity of GSS proteinixnButhionine Sulfoximine results in decreased activity of ACO2 proteinixnButhionine Sulfoximine plays a role in or acts as a marker for Heart Septal Defects, VentricularixnTocopherols has a real or putative therapeutic role towards Heart Septal Defects, VentricularixnButhionine Sulfoximine results in decreased expression of ATP2A2 proteinixnButhionine Sulfoximine results in increased expression of BAX proteinixnButhionine Sulfoximine results in decreased expression of BCL2 proteinixnButhionine Sulfoximine results in decreased phosphorylation of GSK3B proteinixnButhionine Sulfoximine results in increased expression of TRP53 protein14687758title0Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis.abstract120Targeted inactivation of the insulin-like hormone 3 (insl3) gene in male mice results in altered gubernacular development, disrupted testis decent, and cryptorchidism. Cryptorchidism is a fairly common human malformation, being displayed in about three males per 100 at birth, but only a small percentage can be linked directly to genetic defects. The phthalate esters (PEs) are high production volume, ubiquitous environmental chemicals, some of which when administered during sexual differentiation, induce male rat reproductive tract malformations including gubernacular agenesis. We hypothesized that phthalate-induced gubernacular lesions likely result from an inhibition of insl3 gene expression. Three phthalates, di-n-ethylhexyl phthalate (DEHP), dibutyl phthalate (DBP) and benzyl butyl phthalate (BBP) were administered orally to the dam on gestation day 14 through 18 (GD14-18) and the fetal testes examined on GD18 for effects on steroid hormone production and insl3 gene expression. Compared to chemicals like vinclozolin, linuron, and prochloraz that act as AR antagonists and/or inhibit fetal Leydig cell testosterone production, only the three phthalates significantly reduced both ex vivo testosterone production and insl3 gene expression when quantified by real-time rtPCR. These results provide the first demonstration of PE-induced alteration of insl3 mRNA in the fetal male rat testis.chemVINCLOZOLINchemDIBUTYL PHTHALATEchemBUTYLBENZYL PHTHALATEchemPROCHLORAZchemLINURONchemDIETHYLHEXYL PHTHALATEdiseaseCRYPTORCHIDISMgeneARgeneINSL3action termexpressionaction termbindingaction termactivityixnINSL3 plays a role in or acts as a marker for CryptorchidismixnDiethylhexyl Phthalate results in decreased expression of INSL3 mRNAixnDibutyl Phthalate results in decreased expression of INSL3 mRNAixnbutylbenzyl phthalate results in decreased expression of INSL3 mRNAixnLinuron does not affect the expression of INSL3 mRNAixnvinclozolin does not affect the expression of INSL3 mRNAixnprochloraz does not affect the expression of INSL3 mRNAixnLinuron binds to and results in decreased activity of AR proteinixnvinclozolin binds to and results in decreased activity of AR proteinixnprochloraz binds to and results in decreased activity of AR protein12704018title0LPS-induced neutrophilic inflammation and Bcl-2 expression in metaplastic mucous cells.abstract88Our previous studies show that Bcl-2, a regulator of apoptosis, may be involved in the reduction of mucous cell metaplasia (MCM) during recovery from inflammatory responses. The present study was to determine whether neutrophilic inflammation mediates Bcl-2 expression in mucous cells. Rats were intratracheally instilled with 50-1000 microg of LPS. The number of neutrophils recovered by bronchoalveolar lavage (BAL) increased with the dose of LPS, and the percentage of Bcl-2-expressing cells increased with the numbers of neutrophils in the BAL. Depletion of neutrophils did not reduce MCM, but the percentage of Bcl-2-positive cells increased 1.8-fold in neutrophil-depleted compared with controls. Injection of rats with bezafibrate, an inducer of cytochrome P-450, doubled the number of neutrophils in the BAL, decreased MCM twofold compared with vehicle-injected controls, and reduced Bcl-2 expression. Bcl-2 mRNA levels decreased in a tracheal epithelial cell line treated with bezafibrate. These data demonstrate that Bcl-2 expression is independent of the number of neutrophils in the BAL and that bezafibrate may directly reduce Bcl-2 expression in epithelial cells.chemBEZAFIBRATEchemLIPOPOLYSACCHARIDESdiseaseMETAPLASIAdiseaseINFLAMMATIONgeneIL1BgeneBCL2action termreactionaction termexpressionixnBCL2 plays a role in or acts as a marker for MetaplasiaixnBezafibrate results in increased expression of IL1B proteinixnBezafibrate has a real or putative therapeutic role towards InflammationixnLipopolysaccharides plays a role in or acts as a marker for MetaplasiaixnBezafibrate inhibits the reaction [Lipopolysaccharides results in increased expression of BCL2 protein]ixnLipopolysaccharides plays a role in or acts as a marker for InflammationixnLipopolysaccharides results in increased expression of BCL2 proteinixnBezafibrate results in decreased expression of BCL2 mRNAixnLipopolysaccharides results in increased expression of IL1B protein17101059title0Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A3 adenosine receptor expression.abstract119Methotrexate (MTX) exerts an anti-inflammatory effect via its metabolite adenosine, which activates adenosine receptors. The A3 adenosine receptor (A3AR) was found to be highly expressed in inflammatory tissues and peripheral blood mononuclear cells (PBMCs) of rats with adjuvant-induced arthritis (AIA). CF101 (IB-MECA), an A3AR agonist, was previously found to inhibit the clinical and pathological manifestations of AIA. The aim of the present study was to examine the effect of MTX on A3AR expression level and the efficacy of combined treatment with CF101 and MTX in AIA rats. AIA rats were treated with MTX, CF101, or both agents combined. A3AR mRNA, protein expression and exhibition were tested in paw and PBMC extracts from AIA rats utilizing immunohistochemistry staining, RT-PCR and Western blot analysis. A3AR level was tested in PBMC extracts from patients chronically treated with MTX and healthy individuals. The effect of CF101, MTX and combined treatment on A3AR expression level was also tested in PHA-stimulated PBMCs from healthy individuals and from MTX-treated patients with rheumatoid arthritis (RA). Combined treatment with CF101 and MTX resulted in an additive anti-inflammatory effect in AIA rats. MTX induced A2AAR and A3AR over-expression in paw cells from treated animals. Moreover, increased A3AR expression level was detected in PBMCs from MTX-treated RA patients compared with cells from healthy individuals. MTX also increased the protein expression level of PHA-stimulated PBMCs from healthy individuals. The increase in A3AR level was counteracted in vitro by adenosine deaminase and mimicked in vivo by dipyridamole, demonstrating that receptor over-expression was mediated by adenosine. In conclusion, the data presented here indicate that MTX induces increased A3AR expression and exhibition, thereby potentiating the inhibitory effect of CF101 and supporting combined use of these drugs to treat RA.chemDIPYRIDAMOLEchemMETHOTREXATEchemCF101diseaseINFLAMMATIONgeneADORA3geneADORA2Aaction termexpressionaction termbindingaction termactivityixnMethotrexate results in increased expression of ADORA2A proteinixnMethotrexate has a real or putative therapeutic role towards InflammationixnMethotrexate results in increased expression of ADORA3 mRNAixnCF101 results in decreased expression of ADORA3 mRNAixnMethotrexate results in increased expression of ADORA3 proteinixnMethotrexate results in increased expression of ADORA3 proteinixnCF101 has a real or putative therapeutic role towards InflammationixnCF101 results in decreased expression of ADORA3 proteinixnDipyridamole results in increased expression of ADORA3 proteinixnCF101 binds to and results in increased activity of ADORA3 protein18854779title0Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin.abstract139PURPOSE: High-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC) has been developed as a possible curative treatment modality in several solid tumours. However, a large interindividual variability in toxicity is encountered in high-dose chemotherapy. A priori identification of patients at risk for toxicity could be an attractive prospect. Genotyping of genes encoding drug-metabolising enzymes might provide such a tool.
EXPERIMENTAL DESIGN: We assessed 16 selected polymorphisms in nine genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) of putative relevance in CTC metabolism using polymerase chain reaction and DNA sequencing in 113 patients who were treated with high-dose chemotherapy regimens based on CTC.
RESULTS: Patients heterozygous for the ALDH3A1*2 allele (allelic frequency 21.2%) had an increased risk of haemorrhagic cystitis when compared with patients with wild-type alleles [5/38 vs. 1/70; odds ratio (OR): 11.95, 95% confidence interval (CI): 1.18-120.56; P=0.04]. Furthermore, patients heterozygous for the ALDH1A1*2 allele (allelic frequency 5.8%) had an increased risk of liver toxicity when compared with patients with wild-type alleles (6/13 vs. 19/99; OR: 5.13, 95% CI: 1.30-20.30; P=0.02). No other relations reached significance.
CONCLUSION: Patients heterozygous for the ALDH3A1*2 and ALDH1A1*2 allele have an increased risk of haemorrhagic cystitis and liver toxicity, respectively, compared with patients with wild-type alleles when treated with a high-dose chemotherapy combination of CTC. Pharmacogenetic approaches can identify patients who are at risk of experiencing toxic side effects in high-dose chemotherapy.chemTHIOTEPAchemCYCLOPHOSPHAMIDEchemCARBOPLATINdiseaseNEOPLASMSgeneALDH1A1geneALDH3A1action termresponse to substanceixnCyclophosphamide has a real or putative therapeutic role towards NeoplasmsixnThiotepa has a real or putative therapeutic role towards NeoplasmsixnCarboplatin has a real or putative therapeutic role towards NeoplasmsixnALDH3A1 protein affects the susceptibility to CyclophosphamideixnALDH3A1 protein affects the susceptibility to ThiotepaixnALDH3A1 protein affects the susceptibility to CarboplatinixnALDH1A1 protein affects the susceptibility to CyclophosphamideixnALDH1A1 protein affects the susceptibility to ThiotepaixnALDH1A1 protein affects the susceptibility to Carboplatin19567381title0Rapamycin promotes arterial thrombosis in vivo: implications for everolimus and zotarolimus eluting stents.abstract108AIMS: Drug-eluting stents (DES) may be associated with an increased risk for stent thrombosis when compared with bare-metal stents. In endothelial cells, rapamycin induces tissue factor (TF) by inhibiting the mammalian target of rapamycin (mTOR). However, the effect of mTOR inhibition on TF activity and thrombus formation in vivo has not yet been studied. Moreover, it is unclear whether second-generation DES substances everolimus and zotarolimus have an effect on endothelial TF expression.
METHODS AND RESULTS: In a mouse carotid artery photochemical injury model, rapamycin (182 +/- 27.5 microg/L) decreased time to thrombotic occlusion by 40%, increased TF activity, and abrogated p70S6K phosphorylation when compared with controls. In vitro, rapamycin, everolimus, and zotarolimus (each 10(-7) mol/l) enhanced TNF-alpha-induced TF expression by 2.2-, 1.7-, and 2.4-fold, respectively, which was paralleled by an increase in TF surface activity. Similar to rapamycin, everolimus and zotarolimus abrogated TNF-alpha-induced p70S6K phosphorylation under these conditions.
CONCLUSION: Rapamycin increases TF activity and promotes arterial thrombosis in vivo at concentrations relevant in patients undergoing DES implantation; this effect may increase the thrombogenicity of DES. Since everolimus and zotarolimus augment endothelial TF expression and activity in vitro in a similar manner as rapamycin, these findings may also be relevant for second generation DES.chemSIROLIMUSchemEVEROLIMUSchemZOTAROLIMUSdiseaseTHROMBOSISgeneMTORgeneF3geneRPS6KB1geneTNFaction termexpressionaction termreactionaction termphosphorylationaction termactivityixnzotarolimus inhibits the reaction [TNF protein results in increased phosphorylation of RPS6KB1 protein]ixnSirolimus results in increased activity of F3 proteinixnSirolimus inhibits the reaction [MTOR protein results in increased phosphorylation of RPS6KB1 protein]ixnSirolimus inhibits the reaction [TNF protein results in increased phosphorylation of RPS6KB1 protein]ixnSirolimus promotes the reaction [TNF protein results in increased expression of F3 protein]ixneverolimus promotes the reaction [TNF protein results in increased expression of F3 protein]ixnSirolimus plays a role in or acts as a marker for ThrombosisixnSirolimus results in decreased activity of MTOR proteinixnzotarolimus promotes the reaction [TNF protein results in increased expression of F3 protein]ixneverolimus inhibits the reaction [TNF protein results in increased phosphorylation of RPS6KB1 protein]18223318title0Proteasome inhibitor Bortezomib induces cell cycle arrest and apoptosis in cell lines derived from Ewing''s sarcoma family of tumors and synergizes with TRAIL.abstract160Bortezomib (VELCADE), formerly known as PS-341, is a novel dipeptide boronic acid proteasome inhibitor with in vitro and in vivo anti-tumor activity. Bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma. In this report, we examined the sensitivity of cell lines derived from Ewing''s sarcoma-family of tumors (ESFT) to Bortezomib. Five ESFT-derived cell lines, TC-71, TC-32, SK-N-MC, A4573 and GRIMES, were highly sensitive to Bortezomib (IC(50) = 20 to 50 nM), and underwent cell cycle arrest and apoptosis following drug treatment. Bortezomib-induced apoptosis was associated with activation of caspase 3, cleavage of PARP and induction of p27 and p21 expression. Moreover, Bortezomib exhibited synergistic activity against the TC-71 and TC-32 cell lines when combined with TRAIL. Our results suggest that Bortezomib might be a useful agent for treatment of ESFT, when used alone or in combination with TRAIL.chemBORTEZOMIBdiseaseLYMPHOMA, MANTLE-CELLdiseaseMULTIPLE MYELOMAgeneCDKN1AgeneCASP3geneCDKN1BgeneTNFSF10action termexpressionaction termcleavageaction termactivityixnbortezomib has a real or putative therapeutic role towards Multiple Myelomaixnbortezomib has a real or putative therapeutic role towards Lymphoma, Mantle-Cellixnbortezomib results in increased activity of CASP3 proteinixnbortezomib results in increased cleavage of CASP3 proteinixnbortezomib results in increased expression of CDKN1A proteinixnbortezomib results in increased expression of CDKN1B protein14972014title0Pro/antioxidant status in murine skin following topical exposure to cumene hydroperoxide throughout the ontogeny of skin cancer.abstract129Organic peroxides used in the chemical and pharmaceutical industries have a reputation for being potent skin tumor promoters and inducers of epidermal hyperplasia. Their ability to trigger free radical generation is critical for their carcinogenic properties. Short-term in vivo exposure of mouse skin to cumene hydroperoxide (Cum-OOH) causes severe oxidative stress and formation of spin-trapped radical adducts. The present study was designed to determine the effectiveness of Cum-OOH compared to 12-O-tetradecanoylphorbol-13-acetate (TPA) in the induction of tumor promotion in the mouse skin, to identify the involvement of cyclooxygenase-2 (COX-2) in oxidative metabolism of Cum-OOH in keratinocytes, and to evaluate morphological changes and outcomes of oxidative stress in skin of SENCAR mice throughout a two-stage carcinogenesis protocol. Dimethyl-benz[a]anthracene (DMBA)-initiated mice were treated with Cum-OOH (32.8 micro mol) or TPA (8.5 nmol) twice weekly for 20 weeks to promote papilloma formation. Skin carcinoma formed only in DMBA/Cum-OOH-exposed mice. Higher levels of oxidative stress and inflammation (as indicated by the accumulation of peroxidative products, antioxidant depletion, and edema formation) were evident in the DMBA/Cum-OOH group compared to DMBA/TPA treated mice. Exposure of keratinocytes (HaCaT) to Cum-OOH for 18 h resulted in expression of COX-2 and increased levels of PGE(2). Inhibitors of COX-2 efficiently suppressed oxidative stress and enzyme expression in the cells treated with Cum-OOH. These results suggest that COX-2-dependent oxidative metabolism is at least partially involved in Cum-OOH-induced inflammatory responses and thus tumor promotion.chem9,10-DIMETHYL-1,2-BENZANTHRACENEchemN-(2-CYCLOHEXYLOXY-4-NITROPHENYL)METHANESULFONAMIDEchemCUMENE HYDROPEROXIDEchemDINOPROSTONEdiseaseEDEMAdiseaseSKIN NEOPLASMSdiseaseINFLAMMATIONgeneMPOgenePTGS2action termreactionaction termexpressionaction termcotreatmentaction termactivityaction termabundanceixncumene hydroperoxide plays a role in or acts as a marker for Skin Neoplasmsixncumene hydroperoxide plays a role in or acts as a marker for Edemaixn9,10-Dimethyl-1,2-benzanthracene plays a role in or acts as a marker for Edemaixncumene hydroperoxide results in increased expression of PTGS2 proteinixnN-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide inhibits the reaction [cumene hydroperoxide results in increased expression of PTGS2 protein]ixn9,10-Dimethyl-1,2-benzanthracene plays a role in or acts as a marker for Skin Neoplasmsixn9,10-Dimethyl-1,2-benzanthracene plays a role in or acts as a marker for Inflammationixncumene hydroperoxide plays a role in or acts as a marker for Inflammationixn[cumene hydroperoxide results in increased expression of PTGS2 protein] which results in increased abundance of Dinoprostoneixn[9,10-Dimethyl-1,2-benzanthracene co-treated with cumene hydroperoxide] results in increased activity of MPO protein12770949title0A comparison of Ca2+ channel blocking mode between gabapentin and verapamil: implication for protection against hypoxic injury in rat cerebrocortical slices.abstract1581 The mode of Ca(2+) channel blocking by gabapentin [1-(aminomethyl)cyclohexane acetic acid] was compared to those of other Ca(2+) channel blockers, and the potential role of Ca(2+) channel antagonists in providing protection against hypoxic injury was subsequently investigated in rat cerebrocortical slices. 2 mRNA for the alpha(2)delta subunits of Ca(2+) channels was found in rat cerebral cortex. 3 Nitric oxide (NO) synthesis estimated from cGMP formation was enhanced by KCl stimulation, which was mediated primarily by the activation of N- and P/Q-type Ca(2+) channels. Gabapentin blocked both types of Ca(2+) channels, and preferentially reversed the response to 30 mM K(+) stimulation compared with 50 mM K(+) stimulation. In contrast, verapamil preferentially inhibited the response to depolarization by the higher concentration (50 mM) of K(+). 4 Gabapentin inhibited KCl-induced elevation of intracellular Ca(2+) in primary neuronal culture. 5 Hypoxic injury was induced in cerebrocortical slices by oxygen deprivation in the absence (severe injury) or presence of 3 mM glucose (mild injury). Gabapentin preferentially inhibited mild injury, while verapamil suppressed only severe injury. omega-Conotoxin GVIA (omega-CTX) and omega-agatoxin IVA (omega-Aga) were effective in both models. 6 NO synthesis was enhanced in a manner dependent on the severity of hypoxic insults. Gabapentin reversed the NO synthesis induced by mild insults, while verapamil inhibited that elicited by severe insults. omega-CTX and omega-Aga were effective in both the cases. 7 Therefore, the data suggest that gabapentin and verapamil cause activity-dependent Ca(2+) channel blocking by different mechanisms, which are associated with their cerebroprotective actions and are dependent on the severity of hypoxic insults.chemNITRIC OXIDEchemPOTASSIUM CHLORIDEchemGABAPENTINchemOMEGA-CONOTOXIN GVIAchemOMEGA-AGATOXIN IVAchemGLUCOSEchemVERAPAMILdiseaseANOXIAgeneCACNA1BgeneCACNA1Aaction termreactionaction termactivityaction termabundanceixnCACNA1B protein affects the reaction [Potassium Chloride results in increased abundance of Nitric Oxide]ixngabapentin has a real or putative therapeutic role towards Anoxiaixngabapentin results in decreased activity of CACNA1A proteinixnomega-Agatoxin IVA has a real or putative therapeutic role towards Anoxiaixnomega-Conotoxin GVIA has a real or putative therapeutic role towards Anoxiaixngabapentin results in decreased activity of CACNA1B proteinixnVerapamil has a real or putative therapeutic role towards AnoxiaixnCACNA1A protein affects the reaction [Potassium Chloride results in increased abundance of Nitric Oxide]ixnGlucose plays a role in or acts as a marker for Anoxia20404010title0Bezafibrate mildly stimulates ketogenesis and fatty acid metabolism in hypertriglyceridemic subjects.abstract102Our objective was to determine whether bezafibrate, a hypotriglyceridemic drug and peroxisome proliferator-activated receptor (PPAR)-alpha agonist, is ketogenic and increases fatty acid oxidation in humans. We measured fatty acid metabolism and ketone levels in 13 mildly hypertriglycemic adults (67 +/- 11 years old) during 2 metabolic study days lasting 6 h, 1 day before and 1 day after bezafibrate (400 mg of bezafibrate per day for 12 weeks). beta-Hydroxybutyrate, triglycerides, free fatty acids, fatty acid profiles, insulin, and glucose were measured in plasma, and fatty acid beta-oxidation was measured in breath after an oral 50-mg dose of the fatty acid tracer [U-(13)C]linoleic acid. As expected, 12 weeks on bezafibrate decreased plasma triglycerides by 35%. Bezafibrate tended to raise postprandial beta-hydroxybutyrate, an effect that was significant after normalization to the fasting baseline values (p = 0.03). beta-Oxidation of [U-(13)C]linoleic acid increased by 30% (p = 0.03) after treatment. On the metabolic study day after bezafibrate treatment, postprandial insulin decreased by 26% (p = 0.01), and glucose concentrations were lower 2 to 5 h postprandially. Thus, in hypertriglyceridemic individuals, bezafibrate is mildly ketogenic and significantly changes fatty acid metabolism, effects that may be linked to PPARalpha stimulation and to moderately improved glucose metabolism.chemTRIGLYCERIDESchemLINOLEIC ACIDchemGLUCOSEchemBEZAFIBRATEchem3-HYDROXYBUTYRIC ACIDchemKETONESdiseaseHYPERTRIGLYCERIDEMIAdiseaseGLUCOSE METABOLISM DISORDERSgenePPARAgeneINSaction termexpressionaction termoxidationaction termbindingaction termactivityaction termabundanceixn[Bezafibrate binds to and results in increased activity of PPARA protein] which results in decreased abundance of TriglyceridesixnBezafibrate has a real or putative therapeutic role towards Glucose Metabolism Disordersixn[Bezafibrate binds to and results in increased activity of PPARA protein] which results in increased abundance of 3-Hydroxybutyric Acidixn[Bezafibrate binds to and results in increased activity of PPARA protein] which results in decreased expression of INS proteinixnBezafibrate has a real or putative therapeutic role towards Hypertriglyceridemiaixn[Bezafibrate binds to and results in increased activity of PPARA protein] which results in increased oxidation of Linoleic AcidixnBezafibrate binds to and results in increased activity of PPARA proteinixn[Bezafibrate binds to and results in increased activity of PPARA protein] which results in increased abundance of Ketonesixn[Bezafibrate binds to and results in increased activity of PPARA protein] which results in decreased abundance of Glucose20355050title0Aqueous extract of Hibiscus sabdariffa L. decelerates acetaminophen-induced acute liver damage by reducing cell death and oxidative stress in mouse experimental models.abstract169BACKGROUND: Acetaminophen (AAP)-induced oxidative stress can cause cell death to induce liver damage. The antioxidant effect of Hibiscus sabdariffa L. (HS) was shown in previous studies. In this study the effect of HS extract (HSE) on AAP-induced liver injury in BALB/c mice was investigated.
RESULTS: In vivo, BALB/c mice were fed orally with 200, 400 or 600 mg kg(-1) HSE for 2 weeks and then injected with 1000 mg kg(-1) AAP. Pretreatment with HSE decreased lipid peroxidation and increased catalase activity and glutathione level. It also decreased AAP-induced liver injury, accompanied by decreased expression of pJNK, Bax and tBid in the liver. Additionally, HSE protected BALB/c normal liver cells from AAP-induced damage in vitro.
CONCLUSION: It has been demonstrated that HSE can protect the mouse liver from AAP-induced injury and that the protective mechanism might involve decreasing oxidative stress and reducing cell death.chemGLUTATHIONEchemACETAMINOPHENchemPLANT EXTRACTSdiseaseDRUG-INDUCED LIVER INJURYgeneCATgeneBAXgeneBIDaction termreactionaction termexpressionaction termactivityixnAcetaminophen plays a role in or acts as a marker for Drug-Induced Liver InjuryixnAcetaminophen results in increased expression of BAX proteinixnPlant Extracts inhibits the reaction [Acetaminophen results in increased expression of BAX protein]ixnPlant Extracts results in increased activity of CAT proteinixnPlant Extracts has a real or putative therapeutic role towards Drug-Induced Liver InjuryixnAcetaminophen results in increased expression of BID proteinixnPlant Extracts inhibits the reaction [Acetaminophen results in increased expression of BID protein]20110775title0Bortezomib blocks the catabolic process of autophagy via a cathepsin-dependent mechanism, affects endoplasmic reticulum stress and induces caspase-dependent cell death in antiestrogen-sensitive and resistant ER+ breast cancer cells.abstract233In recent studies, we and others showed that autophagy is critical to estrogen receptor positive (ER+) breast cancer cell survival and the development of antiestrogen resistance. Consequently, new approaches are warranted for targeting autophagy in breast cancer cells undergoing antiestrogen therapy. Because crosstalk has been demonstrated between the autophagy- and proteasome-mediated pathways of protein degradation, this study investigated how the proteasome inhibitor bortezomib affects autophagy and cell survival in antiestrogen-treated ER+ breast cancer cells. Bortezomib, at clinically achievable doses, induced a robust death response in ER+, antiestrogen-sensitive and antiestrogen-resistant breast cancer cells undergoing hormonal therapy. Cleavage of PARP and lamin A was detectable as a read-out of cell death, following bortezomib-induced mitochondrial dysfunction. Prior to induction of cell death, bortezomib-treated cells showed high levels of light chain 3 (LC3) and p62, two protein markers for autophagy. The accumulation of these proteins was due to bortezomib-mediated blockade of long-lived protein turnover during macroautophagy. This novel action of bortezomib was linked to its blockade of cathepsin-L activity, which is required for autolysosomal-mediated protein turnover in ER+ breast cancer cells. Further, bortezomib-treated breast cancer cells showed induction of the unfolded protein response, with upregulation of CH OP and GRP78. Bortezomib also induced high levels of the pro-apoptotic protein BNIP3. Knockdown of CH OP and/or BNIP3 expression via RNAi targeting significantly attenuated the death-promoting effects of bortezomib. Thus, bortezomib inhibits prosurvival autophagy, in addition to its known function in blocking the proteasome, and is cytotoxic to hormonally treated ER+ breast cancer cells. These findings indicate that combining a proteasome inhibitor like bortezomib with antiestrogen therapy may have therapeutic advantage in the management of early-stage breast cancer.chemBORTEZOMIBdiseaseBREAST NEOPLASMSgeneLMNAgeneDDIT3genePARP1geneBNIP3geneHSPA5action termexpressionaction termcleavageixnbortezomib results in increased cleavage of PARP1 proteinixnbortezomib results in increased cleavage of LMNA proteinixnbortezomib results in increased expression of HSPA5 proteinixnbortezomib results in increased expression of DDIT3 proteinixnbortezomib results in increased expression of BNIP3 proteinixnbortezomib has a real or putative therapeutic role towards Breast Neoplasms2018554title0Age sensitivity to organophosphate-induced delayed polyneuropathy. Biochemical and toxicological studies in developing chicks.abstract127Young animals are resistant to organophosphate-induced delayed polyneuropathy (OPIDP). The putative target protein in the nervous system for initiation of OPIDP in the adult hen is an enzyme called Neuropathy Target Esterase (NTE), which is dissected by selective inhibitors among nervous tissue esterases hydrolysing phenyl valerate (PV). We report here that the pool of PV-esterases sensitive to paraoxon was different in peripheral nerves of chicks as compared to that of hens while that of brain and spinal cord was not. NTE activity decreased with age in brain, spinal cord and peripheral nerve, but its sensitivity to several inhibitors remained unchanged. In the adult hen more than 70% inhibition of peripheral nerve NTE by neuropathic OPs is followed by deficit of retrograde axonal transport, axonal degeneration and paralysis. Similar NTE inhibition in 40-day-old or younger chicks however is not followed by changes in retrograde axonal transport nor by OPIDP. Chicks aged 60 to 80 days are only marginally sensitive to a single dose of DFP otherwise clearly neuropathic to hens. In vitro and in vivo phosphorylation by DFP and subsequent aging of brain NTE is similar both in chicks and in hens. The recovery of NTE activity monitored in vivo after inhibition by DFP is faster (half-life of about 3 days) in chick peripheral nerves as compared to chick brain, hen brain and hen peripheral nerve (half-life of about 5 days). It is concluded that the reduced sensitivity to OPIDP in chicks is not due to differences in OP-NTE interactions. The resistance might be explained by a more efficient repair mechanism, as suggested by the faster recovery of peripheral nerve NTE activity.chemPOTASSIUM FLUORIDEchemDI-N-BUTYL-2,2-DICHLOROVINYL PHOSPHATEchemMIPAFOXchemISOFLUROPHATEdiseaseNERVE DEGENERATIONdiseaseORGANOPHOSPHATE POISONINGdiseasePOLYNEUROPATHIESgenePNPLA6action termreactionaction termactivityixnmipafox results in decreased activity of PNPLA6 proteinixnIsoflurophate results in decreased activity of PNPLA6 proteinixndi-n-butyl-2,2-dichlorovinyl phosphate results in decreased activity of PNPLA6 proteinixndi-n-butyl-2,2-dichlorovinyl phosphate plays a role in or acts as a marker for Organophosphate PoisoningixnIsoflurophate plays a role in or acts as a marker for Organophosphate Poisoningixnpotassium fluoride inhibits the reaction [Isoflurophate results in decreased activity of PNPLA6 protein]ixndi-n-butyl-2,2-dichlorovinyl phosphate plays a role in or acts as a marker for PolyneuropathiesixnIsoflurophate plays a role in or acts as a marker for Polyneuropathiesixndi-n-butyl-2,2-dichlorovinyl phosphate plays a role in or acts as a marker for Nerve Degeneration9278552title0Induction of nitric oxide synthase in rat intestine by interleukin-1alpha may explain diarrhea associated with zinc deficiency.abstract128Synthesis of inducible nitric oxide synthase (iNOS) in the intestine may result in local tissue damage. We investigated whether a challenge with interleukin-1alpha could give rise to intestinal iNOS expression and diarrhea in rats of differing zinc status. Weaning male rats were fed a zinc-deficient (ZD) diet (2 mg zinc/kg) for 4 wk to induce zinc deficiency or a zinc-supplemented diet [50.8 mg zinc/kg; controls, including pair-fed (PF ) and ad libitum (AL) consumption groups], and then subcutaneously injected with interleukin-1alpha (2 x 10(7) units/kg body wt). Without the interleukin-1alpha challenge, ZD rats had significantly lower plasma zinc concentration than the other groups. Intestinal metallothionein-1 mRNA abundance was lower in ZD rats than in AL rats. iNOS was expressed in the intestine of ZD rats but not in the others. None of the rats experienced diarrhea during the feeding period. Interleukin-1alpha led to a reduction in plasma zinc concentration, enhancement in intestinal metallothionein-1 mRNA levels, and expression of the intestinal iNOS gene in all groups. However, the abundance of iNOS mRNA was significantly higher in ZD rats than in the other groups. The presence of iNOS protein was demonstrated by immunohistochemical staining in the intestine of ZD rats that had been treated with interleukin-1alpha 12 h earlier. In addition, diarrhea occurred in most of the ZD rats and some of the PF rats but not in AL rats after interleukin-1alpha treatment. We conclude that ZD rats respond to interleukin-1alpha challenge more severely than controls, reflected by a more marked and prolonged iNOS expression and a greater incidence of diarrhea.chemZINCdiseaseDERMATITISdiseaseALOPECIAdiseaseDIARRHEAgeneNOS2geneIL1AgeneMT1Aaction termreactionaction termexpressionaction termcotreatmentaction termabundanceixnIL1A plays a role in or acts as a marker for DiarrheaixnZinc deficiency results in decreased expression of MT1A mRNAixnZinc plays a role in or acts as a marker for DiarrheaixnIL1A protein promotes the reaction [Zinc deficiency results in increased expression of NOS2 mRNA]ixnZinc plays a role in or acts as a marker for DermatitisixnZinc deficiency results in increased expression of NOS2 mRNAixnZinc plays a role in or acts as a marker for AlopeciaixnIL1A protein results in increased abundance of ZincixnIL1A protein inhibits the reaction [Zinc deficiency results in decreased expression of MT1A mRNA]ixn[IL1A protein co-treated with Zinc deficiency] results in increased expression of NOS2 protein12750841title0Arsenic trioxide induces apoptosis in cells of MOLT-4 and its daunorubicin-resistant cell line via depletion of intracellular glutathione, disruption of mitochondrial membrane potential and activation of caspase-3.abstract215PURPOSE: To demonstrate that arsenic trioxide (As(2)O(3)) induces apoptosis via a mitochondrial pathway in both parent T lymphoblastoid leukemia MOLT-4 cells and cells of its daunorubicin-resistant subline, MOLT-4/DNR, expressing functional P-gp.
METHODS: Cell growth was measured using an MTT assay. Cell viability was determined using a dye exclusion test. Intracellular glutathione (GSH) was measured using a glutathione assay kit. Mitochondrial membrane potential (MMP) was assessed by rhodamine 123 (Rh123) staining intensity on flow cytometry. Caspase-3 activity was evaluated using a commercially available assay kit on flow cytometry. The percentage of cells undergoing apoptosis was estimated in terms of caspase(+)/PI(-) cells on flow cytometry after assessment for activation of caspase-3 by adding PI.
RESULTS: MOLT-4 cells and MOLT-4/DNR cells were similarly sensitive to the apoptosis-inducing effect of As(2)O(3). Buthionine sulfoxide (BSO) and ascorbic acid (AA) rendered these cells more sensitive to As(2)O(3), whereas N-acetylcysteine (NAC) reduced this sensitivity. BSO and AA decreased, but NAC increased, the intracellular GSH contents of both MOLT-4 and MOLT-4/DNR cells. Decreasing GSH with BSO potentiated As(2)O(3)-mediated growth inhibition, disruption of MMP, activation of caspase-3 and apoptosis of cells. Clinically relevant doses of AA enhanced the anticancer effects of As(2)O(3) via the disruption of MMP, activation of caspase-3, and induction of apoptosis. In contrast, increase GSH levels with NAC attenuated all of these As(2)O(3)-mediated actions.
CONCLUSIONS: The sensitivity of MOLT-4 and MOLT-4/DNR cells to As(2)O(3) was associated with the intracellular GSH content. As(2)O(3) induced apoptosis in parent MOLT-4 cells and MOLT-4/DNR cells expressing functional P-gp via depletion of intracellular GSH, and subsequent disruption of MMP and activation of caspase-3.chemBUTHIONINEchemARSENIC TRIOXIDEchemACETYLCYSTEINEchemASCORBIC ACIDdiseaseLEUKEMIA, LYMPHOIDgeneCASP3action termreactionaction termactivityixnarsenic trioxide results in increased activity of CASP3 proteinixnAscorbic Acid promotes the reaction [arsenic trioxide results in increased activity of CASP3 protein]ixnbuthionine analog promotes the reaction [arsenic trioxide results in increased activity of CASP3 protein]ixnAscorbic Acid has a real or putative therapeutic role towards Leukemia, LymphoidixnAcetylcysteine inhibits the reaction [arsenic trioxide results in increased activity of CASP3 protein]1977408title0Behavioural and neurochemical effects of Ro 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson''s disease.abstract137Behavioural and some neurochemical effects of Ro 40-7592 (3,4-dihydroxy-4''-methyl-5-nitrobenzophenone), a new COMT inhibitor, were studied in rats and mice. Ro 40-7592 increased the effect of L-DOPA (plus benserazide) on locomotor activity, reserpine-induced hypothermia, and catalepsy induced by pimozide, haloperidol and fluphenazine. Locomotor hyperactivity induced by amphetamine or nomifensine, as well as stereotypy induced by amphetamine (but not apomorphine), were also increased by Ro 40-7592. The drug stimulated exploratory activity in the open field test. It decreased the levels of HVA and 3-MT, increased the level of DOPAC but did not change the levels of dopamine in the striatum, nucleus accumbens and frontal cortex. These results indicate that Ro 40-7592 may improve the therapy with L-DOPA (plus decarboxylase inhibitor) of Parkinson''s disease.chemNOMIFENSINEchemPIMOZIDEchemAMPHETAMINEchemTOLCAPONEchemHALOPERIDOLchemFLUPHENAZINEchemRESERPINEchemBENSERAZIDE, LEVODOPA DRUG COMBINATIONdiseaseHYPERKINESISdiseaseSTEREOTYPIC MOVEMENT DISORDERdiseaseCATALEPSYdiseasePARKINSON DISEASEdiseaseHYPOTHERMIAgeneCOMTaction termactivityixntolcapone has a real or putative therapeutic role towards Parkinson Diseaseixnbenserazide, levodopa drug combination has a real or putative therapeutic role towards Parkinson DiseaseixnReserpine plays a role in or acts as a marker for HypothermiaixnPimozide plays a role in or acts as a marker for CatalepsyixnHaloperidol plays a role in or acts as a marker for CatalepsyixnFluphenazine plays a role in or acts as a marker for CatalepsyixnAmphetamine plays a role in or acts as a marker for HyperkinesisixnNomifensine plays a role in or acts as a marker for HyperkinesisixnAmphetamine plays a role in or acts as a marker for Stereotypic Movement Disorderixntolcapone results in decreased activity of COMT protein22564261title0Role of flavin-containing-monooxygenase-dependent neutrophil activation in thioacetamide-induced hepatic inflammation in rats.abstract127Thioacetamide is widely used in industry and is known to be one of the most potent hepatotoxicants in experimental animals. We investigated the involvement of flavin-containing monooxygenase (FMO)-dependent hepatic-neutrophil activation and the release of proinflammatory mediators in thioacetamide-induced hepatic injury in rats. Thioacetamide (100 mg/kg, intraperitoneally) increased, within 12 h, hepatic serum aspartate transferase and alanine transferase levels, tumor necrosis factor- production, interleukin-1 and nitrite levels, and myeloperoxidase activity. Rabbit anti-neutrophil serum markedly inhibited all thioacetamide-altered parameters. In addition, FMO-competitive inhibitor methimazole reduced thioacetamide-induced myeloperoxidase activity, hepatic tumor necrosis factor- , interleukin-1 , nitrite, inducible nitric oxide synthase, and hepatic damage in thioacetamide-treated rats. Thus, we conclude that FMO-dependent hepatic neutrophil activation initiates the release of proinflammatory mediators in thioacetamide-treated rats.chemMETHIMAZOLEchemTHIOACETAMIDEdiseaseDRUG-INDUCED LIVER INJURYgeneNOS2geneTNFgeneMPOgeneIL1Baction termreactionaction termexpressionaction termactivityixnMethimazole inhibits the reaction [Thioacetamide results in increased activity of MPO protein]ixnThioacetamide plays a role in or acts as a marker for Drug-Induced Liver InjuryixnThioacetamide results in increased expression of TNF proteinixnMethimazole inhibits the reaction [Thioacetamide results in increased expression of TNF protein]ixnThioacetamide results in increased expression of IL1B proteinixnThioacetamide results in increased activity of MPO proteinixnMethimazole inhibits the reaction [Thioacetamide results in increased expression of IL1B protein]ixnMethimazole inhibits the reaction [Thioacetamide results in increased expression of NOS2 protein]ixnThioacetamide results in increased expression of NOS2 proteinixnMethimazole has a real or putative therapeutic role towards Drug-Induced Liver Injury17401459title0Sulindac induces apoptosis and inhibits tumor growth in vivo in head and neck squamous cell carcinoma.abstract103Sulindac has antineoplastic effects on various cancer cell lines; consequently, we assessed sulindac''s effects on laryngeal squamous cell carcinoma (SCC) cells in vitro and in vivo. In vitro, SCC (HEP-2) cells treated with various cyclooxygenase inhibitors or transfected with constitutively active signal transducer and activator of transcription 3 (Stat3) or survivin vectors were analyzed using Western blot analysis, annexin V assay, and cell proliferation assay. In parallel, nude mice injected subcutaneously with HEP-2 cells were either treated intraperitoneally with sulindac or left untreated, and analyzed for tumor weight, survivin expression, and tyrosine-phosphorylated Stat3 expression. In vitro studies confirmed the selective antiproliferative and proapoptotic effects of sulindac, which also downregulated Stat3 and survivin protein expression. Stat3 or survivin forced expression partially rescued the antiproliferative effects of sulindac. In vivo studies showed significant repression of HEP-2 xenograft growth in sulindactreated mice versus controls, with near-complete resolution at 10 days. Additionally, tumor specimens treated with sulindac showed downregulation of phosphorylated tyrosine-705 Stat3 and survivin expression. Taken together, our data suggest, for the first time, a specific inhibitory effect of sulindac on tumor growth and survivin expression in laryngeal cancer, both in vitro and in vivo, in a Stat3-dependent manner, suggesting a novel therapeutic approach to head and neck cancer.chemSULINDACdiseaseNEOPLASMS, EXPERIMENTALgeneSTAT3geneBIRC5action termexpressionaction termreactionixnSulindac results in decreased expression of STAT3 proteinixnSulindac results in decreased expression of STAT3 protein modified formixnBIRC5 protein inhibits the reaction [Sulindac results in decreased expression of STAT3 protein modified form]ixnBIRC5 protein inhibits the reaction [Sulindac results in decreased expression of STAT3 protein]ixnSulindac has a real or putative therapeutic role towards Neoplasms, ExperimentalixnSulindac results in decreased expression of BIRC5 protein11994571title0Prothrombotic effects and clinical implications of third-generation oral contraceptives use.abstract93Although the use of oral contraceptives has been frequently associated with an increased risk of thromboembolic events, definitive prothrombotic mechanisms have not so far been fully elucidated. The aim of our investigation was the evaluation of the activities of antithrombin, protein C, protein S and the resistance to activated protein C in 137 healthy users of third-generation oral contraceptives and in 170 healthy women who were not consuming oral contraceptives. Women on oral contraceptives showed a marked prothrombotic pattern, characterized by reduced activities of antithrombin and protein S, and increased resistance to activated protein C. Nearby 50% of oral contraceptive users displayed activities of protein S below the lower value of the reference range (controls, 10%; P < 0.001). No significant differences were observed between two progestagens (desogestrel or gestodene) on the coagulation parameters tested. We believe that, due to the adverse effect on haemostasis, the administration of third-generation oral contraceptives should be carefully considered in women carrying prothrombotic abnormalities.chemETHINYL ESTRADIOLchemETHINYL ESTRADIOL-DESOGESTREL COMBINATIONchemGESTODENEdiseaseTHROMBOPHILIAgenePROS1genePROCgeneSERPINC1action termcotreatmentaction termactivityixnGestodene plays a role in or acts as a marker for Thrombophiliaixnethinyl estradiol-desogestrel combination plays a role in or acts as a marker for ThrombophiliaixnEthinyl Estradiol plays a role in or acts as a marker for Thrombophiliaixnethinyl estradiol-desogestrel combination results in decreased activity of SERPINC1 proteinixnethinyl estradiol-desogestrel combination results in decreased activity of PROS1 proteinixnethinyl estradiol-desogestrel combination results in increased activity of PROC proteinixn[Ethinyl Estradiol co-treated with Gestodene] results in decreased activity of SERPINC1 proteinixn[Ethinyl Estradiol co-treated with Gestodene] results in decreased activity of PROS1 proteinixn[Ethinyl Estradiol co-treated with Gestodene] results in increased activity of PROC protein20709806title0Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis.abstract131Atherosclerosis is a chronic inflammatory disease of the vessel wall. Recent evidence suggests that chronic vascular inflammation ensues as an imbalance between pro- and anti-inflammatory mediators. Recently identified lipid mediators (eg, lipoxins and resolvins) play active roles in promoting the resolution of inflammation. Alterations in vascular smooth muscle cell (VSMC) phenotype, which manifest as a loss of contractile protein expression and increased proliferation and migration, are prominent mechanistic features of both atherosclerosis and restenosis following various interventions (eg, angioplasty and bypass grafting). We sought to determine whether human atherosclerosis is associated with a "resolution deficit" and whether lipoxins and resolvins influence VSMC phenotype. Here we report that plasma levels of aspirin-triggered lipoxin are significantly lower in patients with symptomatic peripheral artery disease than in healthy volunteers. Both aspirin-triggered lipoxin and resolvin E1 block platelet-derived growth factor-stimulated migration of human saphenous vein SMCs and decrease phosphorylation of the platelet-derived growth factor receptor- . Importantly, receptors for aspirin-triggered lipoxin and resolvin E1 (ALX and ChemR23, respectively) were identified in human VSMCs. Overall, these results demonstrate that stimulatory lipid mediators confer a protective phenotypic switch in VSMCs and elucidate new functions for these mediators in the regulation of SMC biology. These results also suggest that peripheral artery disease is associated with an inflammation-resolution deficit and highlight a potential therapeutic opportunity for the regulation of vascular injury responses.chemLIPOXIN A4chem5S,12R,18R-TRIHYDROXY-6Z,8E,10E,14Z,16E-EICOSAPENTAENOIC ACIDdiseaseCORONARY ARTERY DISEASEdiseaseDIABETES MELLITUSdiseasePERIPHERAL ARTERIAL DISEASEgeneCMKLR1geneFPR2genePDGFBgenePDGFRBaction termreactionaction termbindingaction termphosphorylationixn5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid binds to CMKLR1 proteinixnlipoxin A4 binds to FPR2 proteinixn5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid results in decreased phosphorylation of PDGFRB proteinixnPDGFB protein promotes the reaction [5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid results in decreased phosphorylation of PDGFRB protein]ixnlipoxin A4 plays a role in or acts as a marker for Peripheral Arterial Diseaseixnlipoxin A4 results in decreased phosphorylation of PDGFRB proteinixnlipoxin A4 plays a role in or acts as a marker for Diabetes Mellitusixnlipoxin A4 plays a role in or acts as a marker for Coronary Artery DiseaseixnPDGFB protein promotes the reaction [lipoxin A4 results in decreased phosphorylation of PDGFRB protein]21224400title0MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance.abstract131MicroRNAs (miRNAs) are small noncoding RNAs that have important roles in gene regulation. We have previously reported that activin receptor-like kinase 7 (ALK7) and its ligand, Nodal, induce apoptosis in human epithelial ovarian cancer cells. In this study, we examined the regulation of ALK7 by miRNAs and demonstrate that miR-376c targets ALK7. Ectopic expression of miR-376c significantly increased cell proliferation and survival, enhanced spheroid formation and blocked Nodal-induced apoptosis. Interestingly, overexpression of miR-376c blocked cisplatin-induced cell death, whereas anti-miR-376c enhanced the effect of cisplatin. These effects of miR-376c were partially compensated by the overexpression of ALK7. Moreover, in serous carcinoma samples taken from ovarian cancer patients who responded well to chemotherapy, strong ALK7 staining and low miR-376c expression was detected. By contrast, ALK7 expression was weak and miR-376c levels were high in samples from patients who responded poorly to chemotherapy. Finally, treatment with cisplatin led to an increase in expression of mRNA encoding Nodal and ALK7 but a decrease in miR-376c levels. Taken together, these results demonstrate that the Nodal-ALK7 pathway is involved in cisplatin-induced cell death in ovarian cancer cells and that miR-376c enhances proliferation, survival and chemoresistance by targeting, at least in part, ALK7.chemCISPLATINchemCARBOPLATINdiseaseOVARIAN EPITHELIAL CANCERgeneACVR1CgeneMIR376CgeneNODALaction termexpressionaction termreactionaction termresponse to substanceixnCisplatin results in increased expression of ACVR1C mRNAixnACVR1C protein inhibits the reaction [MIR376C results in decreased susceptibility to Cisplatin]ixnNODAL results in increased susceptibility to CarboplatinixnACVR1C results in increased susceptibility to CisplatinixnCisplatin results in decreased expression of MIR376C mRNAixnNODAL results in increased susceptibility to CisplatinixnMIR376C results in decreased susceptibility to CisplatinixnACVR1C results in increased susceptibility to CarboplatinixnCisplatin results in increased expression of NODAL mRNAixnMIR376C plays a role in or acts as a marker for Ovarian epithelial cancer17890024title0BLT-1, a specific inhibitor of the HDL receptor SR-BI, induces a copper-dependent phenotype during zebrafish development.abstract122Block lipid transport-1 (BLT-1) is a small chemical widely used to inhibit the transfer of lipids between high-density lipoproteins (HDL) and cells mediated by scavenger receptor B, type 1 (SR-BI). This study demonstrated that BLT-1 induced in zebrafish (Danio rerio) embryos a copper-dependent phenotype with a twisted notochord, brain ventricle enlargement, and absence of melanisation, phenocopying neocuproine-treated, or calamity mutants. This finding supports an unexpected link between copper availability and SR-BI activity. The copper-chelating activity of BLT-1, revealed by its dramatic effect during embryo development, should be considered in any evaluation of the pharmacological effect of this thiosemicarbazone derivative on SR-BI activity and the potential therapeutic value of this molecule.chemCUPRIC CHLORIDEchemNEOCUPROINEchem2-HEXYL-1-CYCLOPENTANONE THIOSEMICARBAZONEdiseaseABNORMALITIES, MULTIPLEdiseaseHYPOPIGMENTATIONdiseaseNERVOUS SYSTEM MALFORMATIONSgeneSCARB1action termactivityixn2-hexyl-1-cyclopentanone thiosemicarbazone plays a role in or acts as a marker for Nervous System Malformationsixnneocuproine plays a role in or acts as a marker for Nervous System Malformationsixn2-hexyl-1-cyclopentanone thiosemicarbazone plays a role in or acts as a marker for Hypopigmentationixncupric chloride has a real or putative therapeutic role towards Hypopigmentationixnneocuproine plays a role in or acts as a marker for Hypopigmentationixn2-hexyl-1-cyclopentanone thiosemicarbazone results in decreased activity of SCARB1 proteinixn2-hexyl-1-cyclopentanone thiosemicarbazone plays a role in or acts as a marker for Abnormalities, Multipleixnneocuproine plays a role in or acts as a marker for Abnormalities, Multipleixncupric chloride has a real or putative therapeutic role towards Abnormalities, Multipleixncupric chloride has a real or putative therapeutic role towards Nervous System Malformations17089011title0DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a ''functional amplicon'' involving FAS, Her-2/neu and TOP2A genes.abstract214Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (TOP2A) inhibitors doxorubicin and etopoxide (VP-16) demonstrated a 2- to 3-fold increase in FAS promoter activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of FAS promoter following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the FAS promoter was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, FAS promoter activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells.chemETOPOSIDEchemDOXORUBICINchemPACLITAXELchemFLUOROURACILchem4-METHYLENE-2-OCTYL-5-OXOFURAN-3-CARBOXYLIC ACIDchemVINCRISTINEchemCISPLATINdiseaseBREAST NEOPLASMSgeneTOP2AgeneFASNaction termexpressionixnFASN plays a role in or acts as a marker for Breast NeoplasmsixnDoxorubicin results in increased expression of FASN mRNAixnEtoposide results in increased expression of FASN mRNAixnDoxorubicin does not affect the expression of FASN mRNAixnEtoposide does not affect the expression of FASN mRNAixnFluorouracil does not affect the expression of FASN mRNAixnCisplatin does not affect the expression of FASN mRNAixnPaclitaxel does not affect the expression of FASN mRNAixnVincristine does not affect the expression of FASN mRNAixn4-methylene-2-octyl-5-oxofuran-3-carboxylic acid results in decreased expression of TOP2A protein10693666title0Antenatal dexamethasone enhances endothelin receptorB expression in hypoplastic lung in nitrofen-induced diaphragmatic hernia in rats.abstract135BACKGROUND/PURPOSE: The hypoplastic lung and persistent pulmonary hypertension (PPH) are the principle causes of high mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Endothelin-1 (ET-1), which is produced by vascular endothelial cells and some leukocytes, plays a key role in modulating pulmonary vascular tone in PPH. Two different receptors (ET(A) and ET(B)) for ET-1 have been characterized. Binding of ET-1 to ET(A), which is present on smooth muscle cells in fetal lung, results in vasoconstriction. However, binding of ET-1 to ET(B), which is present on endothelial cells results in vasodilation mediated by endogenous nitric oxide. Antenatal glucocorticoid therapy has been shown to prevent abnormal pulmonary arterial structural changes in animal model with CDH. The aim of this study was to investigate the effect of antenatal glucocorticoid administration on ET-1 system in nitrofen-induced CDH hypoplastic lung in rats.
METHODS: A CDH model was induced in pregnant rats after administration of nitrofen on day 9.5 of gestation. Dexamethasone (Dex) was given intraperitoneally on days 18.5 and 19.5 of gestation. Cesarean section was performed on day 21 of gestation. Rat ET-1 protein expression was measured in solubilized lung tissue extracts, by sandwich type enzyme-linked immunosorbent assay (ELISA) analysis. Reverse transcription polymerase chain reaction was performed to evaluate the relative amount of ET-1, ET(A), and ET(B) mRNA expression.
RESULTS: The ET-1 protein and mRNA expression of ET-1 and both receptors were increased significantly in CDH lung compared with controls. Although there was no significant difference in ET(A) mRNA expression between CDH lung with Dex treatment and without Dex treatment, ET(B) mRNA expression was elevated significantly in CDH lung with Dex treatment compared with CDH lung without Dex treatment.
CONCLUSION: These findings suggest that antenatal glucocorticoid therapy may modulate pulmonary vascular tone in CDH hypoplastic lung by selectively upregulating local expression of ET(B).chemDEXAMETHASONEchemNITROFENdiseaseHERNIA, DIAPHRAGMATICgeneEDN1geneEDNRAgeneEDNRBaction termreactionaction termexpressionixnnitrofen plays a role in or acts as a marker for Hernia, DiaphragmaticixnEDN1 plays a role in or acts as a marker for Hernia, DiaphragmaticixnEDNRA plays a role in or acts as a marker for Hernia, DiaphragmaticixnEDNRB plays a role in or acts as a marker for Hernia, DiaphragmaticixnDexamethasone does not affect the reaction [nitrofen results in increased expression of EDNRA mRNA]ixnDexamethasone promotes the reaction [nitrofen results in increased expression of EDNRB mRNA]ixnnitrofen results in increased expression of EDN1 proteinixnnitrofen results in increased expression of EDN1 mRNAixnnitrofen results in increased expression of EDNRA mRNAixnnitrofen results in increased expression of EDNRB mRNA6682440title0Interactions of neurotensin with brain dopamine systems: biochemical and behavioral studies.abstract93Intracisternal (i.c.) injection of neurotensin (NT) to rats or mice attenuated the locomotor hyperactivity induced by d-amphetamine, methylphenidate or cocaine, but not the increased activity induced by apomorphine or lergotrile. The reduction of methylphenidate-induced locomotor activity by i.c. NT was not due to an increased drug metabolism because i.c. NT did not change plasma methylphenidate concentrations. These actions of NT are distinct from those of the dopamine receptor antagonist haloperidol, which blocked the locomotor hyperactivity induced by all five stimulant drugs in rats. A further difference between NT and neuroleptics was demonstrated by the observation that i.c. NT did not block apomorphine-induced stereotypic behavior. In vitro, NT did not displace [3H]spiperone from its binding sites in homogenates of either the striatum or nucleus accumbens from rat brain. Moreover, i.c. injection of NT did not alter the subsequent in vitro binding of [3H]spiperone to membranes of the nucleus accumbens or striatum. In addition, NT did not alter basal or dopamine-stimulated adenylate cyclase activity in homogenates of the nucleus accumbens or striatum. However, i.c. injection of NT produced a significant increase in the concentrations of homovanillic acid, a major dopamine metabolite, in the nucleus accumbens, olfactory tubercles and striatum. In addition, the concentration of dihydroxyphenylacetic acid was increased in the nucleus accumbens and olfactory tubercles after i.c. NT. Peripheral injection of haloperidol produced qualitatively similar effects on dopamine metabolism, but the effects of haloperidol, unlike those of i.c. NT, were attenuated by apomorphine injection. Taken together, these data indicate that centrally administered NT affects certain brain dopamine systems without interacting directly with those dopamine receptors labeled by [3H]spiperone, coupled to adenylate cyclase or mediating the pharmacological effects of apomorphine.chemCOCAINEchemHALOPERIDOLchem3,4-DIHYDROXYPHENYLACETIC ACIDchemLERGOTRILEchemMETHYLPHENIDATEchemAPOMORPHINEchemDEXTROAMPHETAMINEchemHOMOVANILLIC ACIDdiseaseHYPERKINESISgeneNTSaction termabundanceixnNTS has a real or putative therapeutic role towards HyperkinesisixnMethylphenidate plays a role in or acts as a marker for HyperkinesisixnCocaine plays a role in or acts as a marker for Hyperkinesisixnlergotrile plays a role in or acts as a marker for HyperkinesisixnHaloperidol has a real or putative therapeutic role towards HyperkinesisixnApomorphine plays a role in or acts as a marker for HyperkinesisixnDextroamphetamine plays a role in or acts as a marker for HyperkinesisixnNTS protein results in increased abundance of 3,4-Dihydroxyphenylacetic AcidixnNTS protein results in increased abundance of Homovanillic Acid12902993title0SSR181507, a dopamine D2 receptor antagonist and 5-HT1A receptor agonist. II: Behavioral profile predictive of an atypical antipsychotic activity.abstract147SSR181507 ((3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane that displays antagonist activity at dopamine D(2) receptors and agonist activity at 5-HT(1A) receptors. SSR181507 antagonized apomorphine-induced climbing in mice and stereotypies in rats (ED(50) of 2 and 3.4 mg/kg i.p., respectively) and blocked D-amphetamine-induced hyperlocomotion in rats at lower doses (0.3-1 mg/kg i.p.). At 1-10 mg/kg, it was found to disrupt active avoidance in mice. SSR181507 did not induce catalepsy in rats (MED>60 mg/kg i.p.) and antagonized (3-10 mg/kg i.p.) haloperidol-induced catalepsy. SSR181507 was also active in two models sensitive to antidepressant/anxiolytic drugs: in a guinea-pig pup/mother separation test, it decreased (1-3 mg/kg i.p.) the time spent vocalizing during the separation episode, and in a lithium-induced taste aversion procedure in rats, it partially reversed (3 mg/kg i.p.) the decrease of intake of a saccharin solution. Furthermore, SSR181507 increased (3 mg/kg i.p.) the latency time to paradoxical sleep in rats, an effect commonly observed with antidepressants. Coadministration of the selective 5-HT(1A) blocker SL88.0338 produced catalepsy and antagonized the effects of SSR181507 in the depression/anxiety tests, confirming the view that activation of 5-HT(1A) receptors confers an atypical profile on SSR181507, and is responsible for its antidepressant/anxiolytic properties. Finally, SSR181507 (1-3 mg/kg) did not affect memory performance in a Morris water maze task in rats. The pharmacological profile of SSR181507 suggests that it should control the symptoms of schizophrenia, in the absence of extrapyramidal signs and cognitive deficits, with the additional benefit of antidepressant/anxiolytic activities.chem(3-EXO)-8-BENZOYL-N-(((2S)7-CHLORO-2,3-DIHYDRO-1,4-BENZODIOXIN-1-YL)METHYL)-8-AZABICYCLO(3.2.1)OCTANE-3-METHANAMINE MONOHYDROCHLORIDEchemAPOMORPHINEchemSL 88.0338chemDEXTROAMPHETAMINEchemHALOPERIDOLdiseaseANXIETY, SEPARATIONdiseaseHYPERKINESISdiseaseSTEREOTYPIC MOVEMENT DISORDERdiseaseCATALEPSYgeneHTR1AgeneDRD2action termbindingaction termactivityixn(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride binds to and results in decreased activity of DRD2 proteinixnHaloperidol plays a role in or acts as a marker for Catalepsyixn(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride has a real or putative therapeutic role towards Anxiety, SeparationixnDextroamphetamine plays a role in or acts as a marker for HyperkinesisixnSL 88.0338 plays a role in or acts as a marker for Catalepsyixn(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride binds to and results in increased activity of HTR1A proteinixn(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride has a real or putative therapeutic role towards Stereotypic Movement Disorderixn(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride has a real or putative therapeutic role towards HyperkinesisixnApomorphine plays a role in or acts as a marker for Stereotypic Movement Disorderixn(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride plays a role in or acts as a marker for Catalepsy19667237title0Pharmacological activation of soluble guanylate cyclase protects the heart against ischemic injury.abstract100BACKGROUND: The role of the nitric oxide/cGMP/cGMP-dependent protein kinase G pathway in myocardial protection and preconditioning has been the object of intensive investigations. The novel soluble guanylate cyclase activator cinaciguat has been reported to elevate intracellular [cGMP] and activate the nitric oxide/cGMP/cGMP-dependent protein kinase G pathway in vivo. We investigated the effects of cinaciguat on myocardial infarction induced by isoproterenol in rats.
METHODS AND RESULTS: Rats were treated orally twice a day for 4 days with vehicle or cinaciguat (10 mg/kg). Isoproterenol (85 mg/kg) was injected subcutaneously 2 days after the first treatment at an interval of 24 hours for 2 days to produce myocardial infarction. After 17 hours, histopathological observations and left ventricular pressure-volume analysis to assess cardiac function with a Millar microtip pressure-volume conductance catheter were performed, and levels of biochemicals of the heart tissues were measured. Gene expression analysis was performed by quantitative real-time polymerase chain reaction. Isolated canine coronary arterial rings exposed to peroxynitrite were investigated for vasomotor function, and immunohistochemistry was performed for cGMP and nitrotyrosine. The present results show that cinaciguat treatment improves histopathological lesions, improves cardiac performance, improves impaired cardiac relaxation, reduces oxidative stress, ameliorates intracellular enzyme release, and decreases cyclooxygenase 2, transforming growth factor-beta, and beta-actin mRNA expression in experimentally induced myocardial infarction in rats. In vitro exposure of coronary arteries to peroxynitrite resulted in an impairment of endothelium-dependent vasorelaxation, increased nitro-oxidative stress, and reduced intracellular cGMP levels, which were all improved by cinaciguat. A cardioprotective effect of postischemic cinaciguat treatment was shown in a canine model of global ischemia/reperfusion.
CONCLUSIONS: Pharmacological soluble guanylate cyclase activation could be a novel approach for the prevention and treatment of ischemic heart disease.chemISOPROTERENOLchemBAY 58-2667diseaseISCHEMIAdiseaseNECROSISdiseaseMYOCARDIAL INFARCTIONgeneNPPAgenePTGS2geneTGFB1action termreactionaction termexpressionixnIsoproterenol results in increased expression of PTGS2 mRNAixnBAY 58-2667 has a real or putative therapeutic role towards IschemiaixnIsoproterenol plays a role in or acts as a marker for NecrosisixnBAY 58-2667 has a real or putative therapeutic role towards NecrosisixnIsoproterenol plays a role in or acts as a marker for Myocardial InfarctionixnIsoproterenol results in increased expression of NPPA mRNAixnBAY 58-2667 does not affect the reaction [Isoproterenol results in increased expression of NPPA mRNA]ixnBAY 58-2667 inhibits the reaction [Isoproterenol results in increased expression of PTGS2 mRNA]ixnIsoproterenol results in increased expression of TGFB1 mRNAixnBAY 58-2667 inhibits the reaction [Isoproterenol results in increased expression of TGFB1 mRNA]12076251title0The cyclo-oxygenase-2 inhibitor celecoxib perturbs intracellular calcium by inhibiting endoplasmic reticulum Ca2+-ATPases: a plausible link with its anti-tumour effect and cardiovascular risks.abstract194Substantial evidence indicates that the cyclo-oxygenase-2 (COX-2) inhibitor celecoxib, a widely prescribed anti-inflammatory agent, displays anti-tumour effect by sensitizing cancer cells to apoptosis. As part of our effort to understand the mechanism by which celecoxib mediates apoptosis in androgen-independent prostate cancer cells, we investigated its effect on intracellular calcium concentration ([Ca(2+)](i)). Digital ratiometric imaging analysis indicates that exposure of PC-3 cells to celecoxib stimulates an immediate [Ca(2+)](i) rise in a dose- and time-dependent manner. Kinetic data show that this Ca(2+) signal arises from internal Ca(2+) release in conjunction with external Ca(2+) influx. Examinations of the biochemical mechanism responsible for this Ca(2+) mobilization indicate that celecoxib blocks endoplasmic reticulum (ER) Ca(2+)-ATPases. Consequently, inhibition of this Ca(2+) reuptake mechanism results in Ca(2+) mobilization from ER stores followed by capacitative calcium entry, leading to [Ca(2+)](i) elevation. In view of the important role of Ca(2+) in apoptosis regulation, this Ca(2+) perturbation may represent part of the signalling mechanism that celecoxib uses to trigger rapid apoptotic death in cancer cells. This Ca(2+)-ATPase inhibitory activity is highly specific for celecoxib, and is not noted with other COX inhibitors tested, including aspirin, ibuprofen, naproxen, rofecoxib (Vioxx), DuP697 and NS398. Moreover, it is noteworthy that this activity is also observed in many other cell lines examined, including A7r5 smooth muscle cells, NIH 3T3 fibroblast cells and Jurkat T cells. Consequently, this Ca(2+)-perturbing effect may provide a plausible link with the reported toxicities of celecoxib such as increased cardiovascular risks in long-term anti-inflammatory therapy.chemCELECOXIBdiseaseINFLAMMATIONgenePTGS2action termactivityixncelecoxib results in decreased activity of PTGS2 proteinixncelecoxib has a real or putative therapeutic role towards Inflammation21112467title0Case report: delirium due to a diltiazem-fentanyl CYP3A4 drug interaction.abstract75INTRODUCTION: Fentanyl and diltiazem are frequently used medications. Diltiazem inhibits cytochrome P450 3A4 isoenzymes. This can suppress fentanyl metabolism.
METHOD: We present a case of delirium after coadministration of fentanyl and diltiazem.
DISCUSSION: Cautious use is warranted while concomitantly administering fentanyl and diltiazem as this can potentiate fentanyl toxicity. Other 3A4 inhibitors include ketoconazole, erythromycin, nefazodone, ritonavir, delavirdine, aprepitant and imatinib. Psychosomatic medicine psychiatrists, pain and palliative care physicians and cardiologists in particular should be aware of this interaction.chemKETOCONAZOLEchemFENTANYLchemRITONAVIRchemIMATINIBchemDELAVIRDINEchemDILTIAZEMchemNEFAZODONEchemERYTHROMYCINchemAPREPITANTdiseaseDELIRIUMgeneCYP3A4action termactivityixnKetoconazole results in decreased activity of CYP3A4 proteinixnDiltiazem plays a role in or acts as a marker for Deliriumixnaprepitant results in decreased activity of CYP3A4 proteinixnnefazodone results in decreased activity of CYP3A4 proteinixnRitonavir results in decreased activity of CYP3A4 proteinixnFentanyl plays a role in or acts as a marker for DeliriumixnDelavirdine results in decreased activity of CYP3A4 proteinixnDiltiazem results in decreased activity of CYP3A4 proteinixnErythromycin results in decreased activity of CYP3A4 proteinixnimatinib results in decreased activity of CYP3A4 protein16174765title0Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir.abstract130Adult T-cell leukemia (ATL), an aggressive malignancy of CD4+ T cells associated with human T-cell leukemia virus type I (HTLV-I) infection, carries a very poor prognosis because of the resistance of leukemic cells to any conventional regimen, including chemotherapy. We examined the effect of ritonavir, an HIV protease inhibitor, on HTLV-I-infected T-cell lines and primary ATL cells and found that it induced apoptosis and inhibited transcriptional activation of NF-kappaB in these cells. Furthermore, ritonavir inhibited expression of Bcl-xL, survivin, c-Myc, and cyclin D2, the targets of NF-kappaB. In nonobese diabetic/severe combined immunodeficient (NOD/SCID)/gammacnull (NOG) mice, ritonavir very efficiently prevented tumor growth and leukemic infiltration in various organs of NOG mice at the same dose used for treatment of patients with AIDS. Our data indicate that ritonavir has potent anti-NF-kappaB and antitumor effects and might be clinically applicable for treatment of ATL. These results would provide a new concept and novel platform for new drug development of leukemia and solid cancer as well.chemRITONAVIRdiseaseLEUKEMIA-LYMPHOMA, ADULT T-CELLgeneRELgeneMYCgeneNFKB1geneCCND2geneBCL2L1geneRELAgeneBIRC5geneNFKBIAaction termexpressionaction termphosphorylationaction termactivityixnRitonavir has a real or putative therapeutic role towards Leukemia-Lymphoma, Adult T-CellixnRitonavir results in decreased expression of BCL2L1 mRNAixnRitonavir results in decreased expression of BIRC5 mRNAixnRitonavir results in decreased expression of CCND2 mRNAixnRitonavir results in decreased expression of MYC mRNAixnRitonavir results in decreased activity of NFKB1 proteinixnRitonavir results in decreased phosphorylation of NFKBIA proteinixnRitonavir results in decreased activity of REL proteinixnRitonavir results in decreased activity of RELA protein16520986title0A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma.abstract99PURPOSE: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O6-methylguanine-DNA methyltransferase (MGMT). Administration of O6-benzylguanine (O6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O6-BG in combination with BCNU in patients with advanced soft tissue sarcoma.
EXPERIMENTAL DESIGN: Informed consent was obtained from patients with metastatic soft tissue sarcoma na ve to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O6-BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity.
RESULTS: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11-25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9-NR). The most common grade 3-4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells.
CONCLUSIONS: Observed toxicities were consistent with previous studies of O6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.chemO(6)-BENZYLGUANINEchemCARMUSTINEdiseaseNEUTROPENIAdiseaseTHROMBOCYTOPENIAdiseaseTACHYCARDIA, SUPRAVENTRICULARdiseaseANEMIAgeneMGMTaction termactivityixnO(6)-benzylguanine plays a role in or acts as a marker for NeutropeniaixnCarmustine plays a role in or acts as a marker for NeutropeniaixnCarmustine plays a role in or acts as a marker for Tachycardia, SupraventricularixnCarmustine plays a role in or acts as a marker for ThrombocytopeniaixnCarmustine plays a role in or acts as a marker for AnemiaixnO(6)-benzylguanine results in decreased activity of MGMT proteinixnO(6)-benzylguanine plays a role in or acts as a marker for AnemiaixnO(6)-benzylguanine plays a role in or acts as a marker for ThrombocytopeniaixnO(6)-benzylguanine plays a role in or acts as a marker for Tachycardia, Supraventricular19139408title0Retinol saturase promotes adipogenesis and is downregulated in obesity.abstract72Adipocyte differentiation is controlled by many transcription factors, but few known downstream targets of these factors are necessary for adipogenesis. Here we report that retinol saturase (RetSat), which is an enzyme implicated in the generation of dihydroretinoid metabolites, is induced during adipogenesis and is directly regulated by the transcription factor peroxisome proliferator activated receptor gamma (PPARgamma). Ablation of RetSat dramatically inhibited adipogenesis but, surprisingly, this block was not overcome by the putative product of RetSat enzymatic activity. On the other hand, ectopic RetSat with an intact, but not a mutated, FAD/NAD dinucleotide-binding motif increased endogenous PPARgamma transcriptional activity and promoted adipogenesis. Indeed, RetSat was not required for adipogenesis when cells were provided with exogenous PPARgamma ligands. In adipose tissue, RetSat is expressed in adipocytes but is unexpectedly downregulated in obesity, most likely owing to infiltration of macrophages that we demonstrate to repress RetSat expression. Thiazolidinedione treatment reversed low RetSat expression in adipose tissue of obese mice. Thus, RetSat plays an important role in the biology of adipocytes, where it favors normal differentiation, yet is reduced in the obese state. RetSat is thus a novel target for therapeutic intervention in metabolic disease.chemROSIGLITAZONEchemGW 7845chemPIOGLITAZONEdiseaseSIMPSON-GOLABI-BEHMEL SYNDROMEgeneTNFgeneRETSATgenePPARGaction termexpressionaction termbindingaction termactivityixnGW 7845 results in increased expression of RETSAT mRNAixnpioglitazone results in increased expression of RETSAT mRNAixnRETSAT plays a role in or acts as a marker for Simpson-Golabi-Behmel syndromeixnpioglitazone results in increased expression of RETSAT proteinixn[pioglitazone binds to and results in increased activity of PPARG protein] which results in increased expression of RETSAT mRNAixnrosiglitazone results in increased expression of RETSAT mRNAixnrosiglitazone results in decreased expression of TNF protein21084432title0Coexposure to mercury increases immunotoxicity of trichloroethylene.abstract69We have shown previously that chronic (32 weeks) exposure to occupationally relevant concentrations of the environmental pollutant trichloroethylene (TCE) induced autoimmune hepatitis (AIH) in autoimmune-prone MRL+/+ mice. In real-life, individuals are never exposed to only one chemical such as TCE. However, very little is known about the effects of chemical mixtures on the immune system. The current study examined whether coexposure to another known immunotoxicant, mercuric chloride (HgCl(2)), altered TCE-induced AIH. Female MRL+/+ mice were treated for only 8 weeks with TCE (9.9 or 186.9 mg/kg/day in drinking water) and/or HgCl(2) (260 g/kg/day, sc). Unlike mice exposed to either TCE or HgCl(2) alone, mice exposed to both toxicants for 8 weeks developed significant liver pathology commensurate with early stages of AIH. Disease development in the coexposed mice was accompanied by a unique pattern of anti-liver and anti-brain antibodies that recognized, among others, a protein of approximately 90 kDa. Subsequent immunoblotting showed that sera from the coexposed mice contained antibodies specific for heat shock proteins, a chaperone protein targeted by antibodies in patients with AIH. Thus, although TCE can promote autoimmune disease following chronic exposure, a shorter exposure to a binary mixture of TCE and HgCl(2) accelerated disease development. Coexposure to TCE and HgCl(2) also generated a unique liver-specific antibody response not found in mice exposed to a single toxicant. This finding stresses the importance of including mixtures in assessments of chemical immunotoxicity.chemMERCURIC CHLORIDEchemTRICHLOROETHYLENEdiseaseHEPATITIS, AUTOIMMUNEgeneIFNGgeneSPP1geneBDNFgeneBHMTgeneIL1Baction termexpressionaction termcotreatmentixn[Trichloroethylene co-treated with Mercuric Chloride] results in increased expression of SPP1 proteinixnMercuric Chloride results in increased expression of IFNG proteinixn[Trichloroethylene co-treated with Mercuric Chloride] results in increased expression of BDNF mRNAixnMercuric Chloride plays a role in or acts as a marker for Hepatitis, Autoimmuneixn[Trichloroethylene co-treated with Mercuric Chloride] results in increased expression of IFNG proteinixn[Trichloroethylene co-treated with Mercuric Chloride] results in increased expression of BHMT mRNAixnTrichloroethylene results in increased expression of SPP1 proteinixn[Trichloroethylene co-treated with Mercuric Chloride] results in increased expression of IL1B mRNAixnTrichloroethylene plays a role in or acts as a marker for Hepatitis, Autoimmune21856324title0Manganese nanoparticle activates mitochondrial dependent apoptotic signaling and autophagy in dopaminergic neuronal cells.abstract123The production of man-made nanoparticles for various modern applications has increased exponentially in recent years, but the potential health effects of most nanoparticles are not well characterized. Unfortunately, in vitro nanoparticle toxicity studies are extremely limited by yet unresolved problems relating to dosimetry. In the present study, we systematically characterized manganese (Mn) nanoparticle sizes and examined the nanoparticle-induced oxidative signaling in dopaminergic neuronal cells. Differential interference contrast (DIC) microscopy and transmission electron microscopy (TEM) studies revealed that Mn nanoparticles range in size from single nanoparticles (~25 nM) to larger agglomerates when in treatment media. Manganese nanoparticles were effectively internalized in N27 dopaminergic neuronal cells, and they induced a time-dependent upregulation of the transporter protein transferrin. Exposure to 25-400 g/mL Mn nanoparticles induced cell death in a time- and dose-dependent manner. Mn nanoparticles also significantly increased ROS, accompanied by a caspase-mediated proteolytic cleavage of proapoptotic protein kinase C (PKC ), as well as activation loop phosphorylation. Blocking Mn nanoparticle-induced ROS failed to protect against the neurotoxic effects, suggesting the involvement of other pathways. Further mechanistic studies revealed changes in Beclin 1 and LC3, indicating that Mn nanoparticles induce autophagy. Primary mesencephalic neuron exposure to Mn nanoparticles induced loss of TH positive dopaminergic neurons and neuronal processes. Collectively, our results suggest that Mn nanoparticles effectively enter dopaminergic neuronal cells and exert neurotoxic effects by activating an apoptotic signaling pathway and autophagy, emphasizing the need for assessing possible health risks associated with an increased use of Mn nanoparticles in modern applications.chemBENZYLOXYCARBONYL-VALYL-ALANYL-ASPARTIC ACIDchemMANGANESE COMPOUNDSchemBENZOYLCARBONYL-ASPARTYL-GLUTAMYL-VALYL-ASPARTYL-FLUOROMETHYL KETONEdiseaseNERVE DEGENERATIONgeneTFgeneATG6genePRKD1geneCASP3action termreactionaction termexpressionaction termphosphorylationaction termcleavageaction termactivityixnManganese Compounds results in increased expression of TF proteinixnManganese Compounds results in increased cleavage of and results in increased activity of CASP3 proteinixnbenzyloxycarbonyl-valyl-alanyl-aspartic acid analog inhibits the reaction [Manganese Compounds results in increased cleavage of and results in increased activity of CASP3 protein]ixnManganese Compounds results in increased cleavage of PRKD1 proteinixnbenzyloxycarbonyl-valyl-alanyl-aspartic acid analog inhibits the reaction [Manganese Compounds results in increased cleavage of and results in increased activity of PRKD1 protein]ixnbenzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone inhibits the reaction [Manganese Compounds results in increased cleavage of and results in increased activity of PRKD1 protein]ixnManganese Compounds results in increased phosphorylation of and results in increased activity of PRKD1 proteinixnManganese Compounds results in increased cleavage of ATG6 proteinixnManganese Compounds plays a role in or acts as a marker for Nerve Degeneration17520682title0Promoter methylation as a common mechanism for inactivating E-cadherin in human salivary gland adenoid cystic carcinoma.abstract121BACKGROUND: The role of promoter methylation in the inactivation of E-cadherin (E-cad) in salivary gland adenoid cystic carcinoma (ACC) is unknown. The objective of this study was to determine the role and potential clinical implications of promoter methylation of E-cad in salivary gland ACC.
METHODS: The promoter methylation status of E-cad was determined by using methylation-specific polymerase chain reaction (PCR) analysis in 60 primary salivary gland ACC tissues and 3 ACC cell lines. The level of E-cad protein expression was determined by immunohistochemical analysis of each tumor. E-cad protein and messenger RNA (mRNA) expression levels were examined by immunohistochemical analysis and reverse transcriptase-PCR in 3 ACC cell lines. Associations between molecular alterations and patients'' clinicopathologic characteristics were analyzed statistically. E-cad mRNA expression was examined in a 5-azacytidine-treated ACC-2 cell line.
RESULTS: Promoter methylation of E-cad was detected in 34 of 60 tumors (57%). Of those 34 tumors, 18 tumors (53%) showed no E-cad protein expression, whereas only 5 of the remaining 26 tumors (19%) without E-cad promoter methylation showed no E-cad protein expression (P = .01). Tumors that had E-cad promoter methylation had a significantly higher histologic grade (P = .01) and more perineural invasion (P = .02) compared with tumors that did not have methylation. All 3 ACC cell lines exhibited E-cad promoter methylation and a lack of E-cad mRNA and protein expression, whereas 5-azacytidine restoredE-cad mRNA expression in the ACC-2 cell line.
CONCLUSIONS: E-cad frequently is inactivated in salivary gland ACC through promoter methylation, and E-cad promoter methylation may play a role in tumor cell differentiation and perineural invasion.chemAZACITIDINEdiseaseURINARY BLADDER NEOPLASMSdiseaseNEOPLASM METASTASISdiseaseCARCINOMAdiseaseCARCINOMA, SQUAMOUS CELLdiseaseSALIVARY GLAND NEOPLASMSdiseaseBREAST NEOPLASMSdiseaseCARCINOMA, ADENOID CYSTICgeneCDH1action termexpressionaction termmethylationixnCDH1 plays a role in or acts as a marker for Salivary Gland NeoplasmsixnAzacitidine results in increased expression of CDH1 mRNAixnAzacitidine results in decreased methylation of CDH1 promoterixnCDH1 plays a role in or acts as a marker for Carcinoma, Adenoid CysticixnCDH1 plays a role in or acts as a marker for CarcinomaixnCDH1 plays a role in or acts as a marker for Carcinoma, Squamous CellixnCDH1 plays a role in or acts as a marker for Neoplasm MetastasisixnCDH1 plays a role in or acts as a marker for Urinary Bladder NeoplasmsixnCDH1 plays a role in or acts as a marker for Breast Neoplasms15367699title0Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease.abstract212The thiocarbamate alcoholism drug disulfiram blocks the P-glycoprotein extrusion pump, inhibits the transcription factor nuclear factor-kappaB, sensitizes tumors to chemotherapy, reduces angiogenesis, and inhibits tumor growth in mice. Thiocarbamates react with critical thiols and also complex metal ions. Using melanoma as the paradigm, we tested whether disulfiram might inhibit growth by forming mixed disulfides with critical thiols in a mechanism facilitated by metal ions. Disulfiram given to melanoma cells in combination with Cu2+ or Zn2+ decreased expression of cyclin A and reduced proliferation in vitro at lower concentrations than disulfiram alone. In electrophoretic mobility shift assays, disulfiram decreased transcription factor binding to the cyclic AMP-responsive element in a manner potentiated by Cu2+ ions and by the presence of glutathione, suggesting that thiocarbamates might disrupt transcription factor binding by inducing S-glutathionylation of the transcription factor DNA binding region. Disulfiram inhibited growth and angiogenesis in melanomas transplanted in severe combined immunodeficient mice, and these effects were potentiated by Zn2+ supplementation. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism also induced >50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects. These findings present a novel strategy for treating metastatic melanoma by employing an old drug toward a new therapeutic use.chemCOPPERchemDISULFIRAMdiseaseNEOVASCULARIZATION, PATHOLOGICdiseaseNEOPLASM METASTASISdiseaseMELANOMAgeneCCNA2geneATF2geneCREB1geneATF1action termexpressionaction termreactionaction termcotreatmentaction termactivityixnDisulfiram has a real or putative therapeutic role towards MelanomaixnDisulfiram has a real or putative therapeutic role towards Neovascularization, PathologicixnDisulfiram has a real or putative therapeutic role towards Neoplasm MetastasisixnCopper promotes the reaction [Disulfiram results in decreased activity of CREB1 protein]ixnCopper promotes the reaction [Disulfiram results in decreased activity of ATF1 protein]ixnCopper promotes the reaction [Disulfiram results in decreased activity of ATF2 protein]ixn[Disulfiram co-treated with Copper] results in decreased activity of CREB1 proteinixn[Disulfiram co-treated with Copper] results in decreased activity of ATF1 proteinixn[Disulfiram co-treated with Copper] results in decreased activity of ATF2 proteinixn[Disulfiram co-treated with Copper] results in decreased expression of CCNA2 protein22222932title0Lantana macrophylla Schauer (Verbenaceae) ethanolic extract induces activation of ERK1/2 and p38 MAPKs pathway and Ca2+ imbalance in human trophoblasts derived cell lines.abstract172Lantana macrophylla Schauer (Verbenaceae) a medicinal plant used to treat menstrual and respiratory disorders was investigated. The ethanolic extract from leaves was subjected to phytochemical and biological analysis. BeWo and JEG-3 cells were used to evaluate human chorionic gonadotropin hormone (hCG) production, syncytial formation, Ca2+ uptake and Ca2+ handling protein expression. The cAMP production and the mitogen-activated protein kinases (MAPKs) phosphorylation were also investigated. Phytochemical analysis yield three triterpenes: oleanolic, ursolic and latonolic acid. Viability assay showed no significant cytotoxic effect. A significant decrease in hCG production but not a disturbance on BeWo cell fusion were observed. The cAMP pathway was not affected by L. macrophylla extract alone; although the cAMP production inducted by forskolin was diminished. Both ERK1/2 and p38 MAPKs pathways were activated. Increased intracellular Ca2+ concentration ([Ca2+]i) was observed after 24 h treatment in a time and dose dependent manner; however only L. macrophylla at 10 g/mL induced increased [Ca2+]i after 10 min treatment. CaBP28K and PMCA1/4 were modulated at protein and mRNA levels, respectively. This study showed for the first time the effect of triterpenoids from L. macrophylla leaves on trophoblasts-like cells and indicates a potential toxic effect of this plant in the placental development and fetal growth.chemSB 203580chemPLANT EXTRACTSdiseasePOISONINGdiseaseRESPIRATORY TRACT DISEASESdiseaseDYSMENORRHEAgeneATP2B4geneATP2B1geneCGBgeneMAPK3geneMAPK1geneCALB1action termexpressionixnPlant Extracts has a real or putative therapeutic role towards Respiratory Tract DiseasesixnPlant Extracts has a real or putative therapeutic role towards DysmenorrheaixnPlant Extracts results in decreased expression of CGB proteinixnSB 203580 results in decreased expression of CGB proteinixnPlant Extracts results in increased expression of MAPK1 protein modified formixnPlant Extracts results in increased expression of MAPK3 protein modified formixnPlant Extracts results in increased expression of CALB1 proteinixnPlant Extracts results in increased expression of ATP2B1 mRNAixnPlant Extracts results in increased expression of ATP2B4 mRNAixnPlant Extracts plays a role in or acts as a marker for Poisoning19911120title0Carbon tetrachloride affects inflammation-related biochemical networks in the mouse liver as identified by a customized cDNA microarray system.abstract144OBJECTIVES: We have attempted to upgrade and validate an in-house cDNA microarray system developed by our group for the evaluation of chemical toxicity.
METHODS: To establish an in-house microarray, we selected genes that play pivotal roles in detoxifying exogenous substances and maintaining homeostasis in the liver. To validate the system, we examined gene expression profiles in mouse liver following treatment with different doses of carbon tetrachloride (CCl(4)). The data were also analyzed by pathway analysis tools.
RESULTS: We upgraded our array system by collecting genes that are responsive to xenobiotic receptors, apoptosis-related genes, and stress-responsive genes. The acute toxicity of CCl(4) was confirmed by elevated levels of serum transaminase and histopathological findings. The microarray data showed the CCl(4) treatment induced significant changes in gene expression in the mouse liver, and the ingenuity pathways analysis revealed alterations in gene expression in inflammation-related networks.
CONCLUSIONS: We have established a focused microarray system that may be useful for use in toxicogenomics studies. Using this array system, we gained insight into the mechanisms by which CCl(4) exerts its toxic effects. The results of our study also indicate that the combination of focused arrays and bioinformatics tools is helpful in the mechanistic analysis of chemical toxicity.chemCARBON TETRACHLORIDEdiseaseINFLAMMATIONdiseaseFATTY LIVERdiseaseNECROSISdiseaseDRUG-INDUCED LIVER INJURYgeneCXCL14geneDDIT3geneFTH1geneGADD45AgeneHSPD1action termexpressionixnCarbon Tetrachloride plays a role in or acts as a marker for Fatty LiverixnCarbon Tetrachloride results in increased expression of CXCL14 mRNAixnCarbon Tetrachloride plays a role in or acts as a marker for Drug-Induced Liver InjuryixnCarbon Tetrachloride results in increased expression of DDIT3 mRNAixnCarbon Tetrachloride plays a role in or acts as a marker for NecrosisixnCarbon Tetrachloride results in increased expression of FTH1 mRNAixnCarbon Tetrachloride results in increased expression of HSPD1 mRNAixnCarbon Tetrachloride results in increased expression of GADD45A mRNAixnCarbon Tetrachloride plays a role in or acts as a marker for Inflammation19631748title0The role of MMP-9 in integrin-mediated hippocampal cell death after pilocarpine-induced status epilepticus.abstract108Recent studies demonstrate that matrix metalloproteinase-9 (MMP-9) is closely involved in the pathogenesis of epilepsy. This study investigated the role of MMP-9 in hippocampal cell death after pilocarpine-induced status epilepticus (SE). We showed that MMP-9 expression and activity significantly increased and beta1-integrin levels decreased on day 3 after SE. beta1-integrin degradation was also observed in hippocampal ex vivo extracts incubated with recombinant active MMP-9. Treatment with a selective MMP-9 inhibitor attenuated MMP-9 up-regulation, beta1-integrin degradation, the reduction of ILK activity and Akt phosphorylation, and subsequent hippocampal damage after SE. However, co-treatment with anti-beta1-integrin antibody almost completely blocked the protective effects of the MMP-9 inhibitor on both integrin-mediated survival signaling and hippocampal cell death. Our study demonstrates that MMP-9 induces apoptotic hippocampal cell death by interrupting integrin-mediated survival signaling after SE and suggests that MMP-9 may be a promising target for a neuroprotective approach to preventing seizure-induced hippocampal damage.chemPROTEASE INHIBITORSchemPILOCARPINEdiseaseSTATUS EPILEPTICUSdiseaseBRAIN INJURIESgeneMMP9geneCASP3geneITGB1geneILKaction termreactionaction termexpressionaction termdegradationaction termactivityixnMMP9 plays a role in or acts as a marker for Brain InjuriesixnProtease Inhibitors inhibits the reaction [MMP9 protein results in increased degradation of ITGB1 protein]ixnPilocarpine results in increased activity of MMP9 proteinixnPilocarpine plays a role in or acts as a marker for Status EpilepticusixnPilocarpine results in decreased expression of ITGB1 proteinixnPilocarpine results in increased activity of CASP3 proteinixnPilocarpine results in increased expression of MMP9 proteinixnPilocarpine plays a role in or acts as a marker for Brain InjuriesixnPilocarpine results in decreased activity of ILK protein15726400title0Apoptosis by gemcitabine in non-small cell lung cancer cell line KNS62 is induced downstream of caspase 8 and is profoundly blocked by Bcl-xL over-expression.abstract159BACKGROUND: This study assesses the chemotherapeutic drug gemcitabine in the human non-small cell lung cancer (NSCLC) cell line KNS62 in relation to the CD95-induced apoptotic pathway, and the role of the anti-apoptotic protein Bcl-xL in vitro and in vivo.
MATERIALS AND METHODS: Apoptosis was determined by JAM assay and DAPI staining analysis. Activation of key apoptotic proteins, including caspases 3, 8 and 9 and BID, as well as cytochrome c release and mitochondrial transmembrane potential (MTP), were measured. The impact of the caspase inhibitor zVAD on gemcitabine-induced apoptosis was quantified. The in vitro results were verified in vivo in an orthotopic murine xenotransplantation model.
RESULTS: Gemcitabine treatment, as well as stimulation of CD95, resulted in cleavage of effector caspase 3 as well as its substrate PARP and caspase 9, followed by DNA fragmentation. Cleavage of caspase 8 was demonstrated after CD95 activation but not after the application of gemcitabine. In KNS62-Bcl-xL clones, release of cytochrome c and loss of mitochondrial transmembrane potential were suppressed. Consequently, apoptosis after gemcitabine therapy, as well as CD95-induced apoptosis, were significantly inhibited. Caspase inhibitor zVAD only partly reversed gemcitabine-induced DNA fragmentation. In vivo, there was a significant reduction in tumour volume under gemcitabine therapy. Bcl-xL over-expressing tumours were completely resistant to gemcitabine therapy.
CONCLUSIONS: In NSCLC cell line KNS62 gemcitabine activated the mitochondrial apoptotic pathway downstream of mitochondria without activation of initiator caspases. Bcl-xL over-expression induced significant resistance to gemcitabine. In vivo, the anti-apoptotic effect of Bcl-xL was more pronounced than in vitro. Gemcitabine also induced caspase-independent DNA fragmentation in KNS62 cells.chemBENZYLOXYCARBONYL-VALYL-ALANYL-ASPARTIC ACIDchemGEMCITABINEdiseaseLUNG NEOPLASMSgeneCASP9geneBCL2L1geneCASP3action termcleavageixngemcitabine has a real or putative therapeutic role towards Lung Neoplasmsixngemcitabine results in increased cleavage of CASP3 proteinixngemcitabine results in increased cleavage of CASP9 protein19190346title0Methylation-mediated repression of GADD45alpha in prostate cancer and its role as a potential therapeutic target.abstract114Defects in apoptotic pathway contribute to uncontrolled proliferation of cancer cells and confer resistance to chemotherapy. Growth arrest and DNA damage inducible, alpha (GADD45alpha) is up-regulated on docetaxel treatment and may contribute to docetaxel-mediated cytotoxicity. We examined the mechanism of regulation of GADD45alpha in prostate cancer cells and the effect of its up-regulation on sensitivity to docetaxel chemotherapy. Expression of GADD45alpha in PC3 cells was higher than that in Du145 and LNCaP cells (17- and 12-fold, respectively; P < 0.05). Although the proximal promoter region was unmethylated in all three cell lines, methylation of a 4 CpG region upstream of the proximal promoter correlated inversely with gene expression levels. Methylation was reversed by treatment of Du145 and LNCaP cells with DNA methyltransferase inhibitors, leading to reactivation of GADD45alpha expression in these cells. The 5'' 4 CpG region was also frequently methylated in prostate cancer tissues. Methylation of this region correlated inversely with gene expression in prostate cancer and benign prostate tissues. The methyl binding protein MeCP2 was associated with the methylated 4 CpGs in Du145 cells, and knockdown of MeCP2 in these cells (Du145 MeCP2(-)) led to a significantly increased expression of GADD45alpha (3-fold; P = 0.035) without affecting the methylation status of the gene. Enhanced sensitivity to docetaxel was observed by up-regulation of GADD45alpha in Du145 cells by recombinant expression of GADD45alpha or pretreatment with 5-azacytidine. Our results show that GADD45alpha is epigenetically repressed and is a potential target for treatment of prostate cancer.chemDOCETAXELchemDECITABINEchemAZACITIDINEdiseasePROSTATIC NEOPLASMSgeneGADD45Aaction termexpressionaction termmethylationaction termresponse to substanceixnGADD45A plays a role in or acts as a marker for Prostatic Neoplasmsixn[Azacitidine results in increased expression of GADD45A protein] which results in increased susceptibility to docetaxelixnAzacitidine results in decreased methylation of GADD45A promoterixndecitabine results in decreased methylation of GADD45A promoterixnAzacitidine results in increased expression of GADD45A mRNAixndecitabine results in increased expression of GADD45A mRNAixnAzacitidine results in increased expression of GADD45A proteinixndecitabine results in increased expression of GADD45A proteinixnGADD45A protein results in increased susceptibility to docetaxel17935668title0Antimyeloma effects of resveratrol through inhibition of angiogenesis.abstract71BACKGROUND: In multiple myeloma (MM), bone marrow angiogenesis parallels tumour progression and correlates with disease activity. Recent studies have proved resveratrol possesses antiangiogenic activity in vitro and in vivo. In this study, we examined the effects of resveratrol on myeloma cell dependent angiogenesis and the effects of resveratrol on some important angiogenic factors of RPMI 8226 cells.
METHODS: RPMI 8226 cells were cocultured with human umbilical vein endothelial cells (HUVECs) to evaluate the effects of myeloma cells on angiogenesis. The RPMI 8226 cells were treated with various concentrations of resveratrol (6.25 - 50.00 micromol/L) for different times (12 - 72 hours). Reverse transcriptase polymerase chain reaction (RT-PCR) was used to assay vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), metalloproteinases (MMP)-2 and MMP-9 mRNA. Gelatin zymography was used to analyze MMP-2 and MMP-9 activity. VEGF and bFGF proteins secreted by the cells in the medium were quantified by enzyme linked immunosorbent assay (ELISA).
RESULTS: Cell proliferation, migration and differentiation of HUVECs markedly increased by coculture with RPMI 8226 cells. Resveratrol inhibited proliferation, migration and tube formation of HUVECs cocultured with myeloma cells in a dose dependent manner. Treatment of RPMI 8226 cells with resveratrol caused a decrease in MMP-2 and MMP-9 activity. Resveratrol inhibited VEGF and bFGF protein expression in a dose and time dependent manner. Furthermore, decreased levels of VEGF, bFGF, MMP-2 and MMP-9 mRNA from cells treated with various concentrations of resveratrol confirmed its antiangiogenic action at the level of gene expression.
CONCLUSIONS: Resveratrol inhibits multiple myeloma angiogenesis by regulating expression and secretion of VEGF, bFGF, MMP-2 and MMP-9. Resveratrol may be a potential candidate for the treatment of multiple myeloma.chemRESVERATROLdiseaseMULTIPLE MYELOMAgeneFGF2geneMMP9geneMMP2geneVEGFAaction termexpressionaction termsecretionaction termactivityixnresveratrol has a real or putative therapeutic role towards Multiple Myelomaixnresveratrol results in decreased activity of MMP2 proteinixnresveratrol results in decreased activity of MMP9 proteinixnresveratrol results in decreased expression of and results in decreased secretion of VEGFA proteinixnresveratrol results in decreased expression of FGF2 proteinixnresveratrol results in decreased expression of VEGFA mRNAixnresveratrol results in decreased expression of FGF2 mRNAixnresveratrol results in decreased expression of MMP2 mRNAixnresveratrol results in decreased expression of MMP9 mRNA17255338title0Activation of peroxisome proliferator-activated receptor gamma contributes to the survival of T lymphoma cells by affecting cellular metabolism.abstract145Peroxisome proliferator-activated receptor gamma (PPARgamma) is a metabolic regulator involved in maintaining glucose and fatty acid homeostasis. Besides its metabolic functions, the receptor has also been implicated in tumorigenesis. Ligands of PPARgamma induce apoptosis in several types of tumor cells, leading to the proposal that these ligands may be used as antineoplastic agents. However, apoptosis induction requires high doses of ligands, suggesting the effect may not be receptor-dependent. In this report, we show that PPARgamma is expressed in human primary T-cell lymphoma tissues and activation of PPARgamma with low doses of ligands protects lymphoma cells from serum starvation-induced apoptosis. The prosurvival effect of PPARgamma was linked to its actions on cellular metabolic activities. In serum-deprived cells, PPARgamma attenuated the decline in ATP, reduced mitochondrial hyperpolarization, and limited the amount of reactive oxygen species (ROS) in favor of cell survival. Moreover, PPARgamma regulated ROS through coordinated transcriptional control of a set of proteins and enzymes involved in ROS metabolism. Our study identified cell survival promotion as a novel activity of PPARgamma. These findings highlight the need for further investigation into the role of PPARgamma in cancer before widespread use of its agonists as anticancer therapeutics.chemROSIGLITAZONEdiseaseLYMPHOMA, T-CELLgeneCASP3geneNCF2genePPARGgeneUCP2geneSOD2action termexpressionaction termactivityixnrosiglitazone results in increased activity of SOD2 proteinixnrosiglitazone results in decreased expression of NCF2 proteinixnPPARG plays a role in or acts as a marker for Lymphoma, T-Cellixnrosiglitazone results in decreased activity of CASP3 proteinixnrosiglitazone results in increased expression of UCP2 mRNAixnrosiglitazone results in increased activity of PPARG proteinixnrosiglitazone results in decreased expression of NCF2 mRNAixnrosiglitazone results in increased expression of UCP2 proteinixnrosiglitazone results in increased expression of SOD2 mRNA7967349title0Effects of endothelin-1 on renal function in humans: implications for physiology and pathophysiology.abstract102Elevated levels of the vasocontrictor peptide endothelin-1 have been demonstrated in various pathological conditions that are characterized by sodium retention and/or renal vasoconstriction, such as heart failure, hepatorenal syndrome, renal failure and during administration of cyclosporin and radiocontrast. In the present study we studied in seven healthy subjects the renal and endocrine effects of systemic administration of endothelin-1 (0.5, 1.0 and 2.5 ng/kg/min). During endothelin-1 infusion plasma levels rose from 3.2 +/- 0.5 to respectively 5.0 +/- 0.8, 6.2 +/- 0.5 and 8.5 +/- 1.1 pmol/liter, values that can also be observed in physiological and pathological conditions. Infusion of low dosages of endothelin-1, that result in a twofold increase in plasma levels, decreased sodium excretion by 36%, without a significant effect on systemic and renal hemodynamics. Infusion of 2.5 ng/kg/min of endothelin-1 further enhanced sodium retention and, in addition, increased renal vascular resistance by 37%. Blood pressure did not change significantly. Pretreatment with the calcium channel blocker nifedipine caused renal vasodilation, which compensated for the renal vasocontriction by endothelin-1 and prevented sodium retention. Apparently, endothelin-1 participates in volume homeostasis in human, whereas pathophysiological concentrations can contribute to renal vasoconstriction and sodium retention. Calcium channel blockers may protect against these effects of endothelin-1.chemNIFEDIPINEchemCYCLOSPORINEchemCONTRAST MEDIAdiseaseRENAL INSUFFICIENCYdiseaseHEART FAILUREdiseaseHEPATORENAL SYNDROMEgeneEDN1action termexpressionixnEDN1 plays a role in or acts as a marker for Renal InsufficiencyixnEDN1 plays a role in or acts as a marker for Hepatorenal SyndromeixnEDN1 plays a role in or acts as a marker for Heart FailureixnContrast Media results in increased expression of EDN1ixnCyclosporine results in increased expression of EDN115541506title0Inhibition of key cytokines by tetrathiomolybdate in the bleomycin model of pulmonary fibrosis.abstract96Tetrathiomolybdate is an anticopper drug with a unique mechanism of action. Tetrathiomolybdate complexes copper to protein and itself, rendering the copper unavailable for cellular uptake. It was originally developed for Wilson''s disease, and is now being developed as an antiangiogenic agent for the treatment of cancer. Many angiogenic cytokines require normal levels of copper, and lowered copper levels reduce cytokine signaling while cellular copper requirements are met. Cytokines of fibrosis and inflammation may be similarly copper dependent, since tetrathiomolybdate inhibits bleomycin induced pulmonary inflammation and fibrosis. The basis for this inhibition was evaluated here by examination of tetrathiomolybdate effects on cytokines in lung pathophysiologically important in the bleomycin mouse model of pulmonary damage. Results in mice injected endotracheally with bleomycin confirmed that tetrathiomolybdate therapy was effective in reducing fibrosis. This effect was associated with significant inhibition of bleomycin-induced tumor necrosis factor alpha and transforming growth factor beta expression in lung homogenates. These effects were shown to be independent of one another. This indicates that tetrathiomolybdate therapy can be effective even when fibrosis is at a more chronic stage, wherein inflammatory cytokines are playing a diminishing role. The inhibition of tumor necrosis factor alpha suggests that diseases of tumor necrosis factor alpha overexpression are also potential targets of tetrathiomolybdate therapy.chemTETRATHIOMOLYBDATEchemBLEOMYCINdiseasePULMONARY FIBROSISgeneCCL2geneTGFB1geneTNFaction termexpressionaction termreactionixnBleomycin results in increased expression of TNF mRNAixnBleomycin results in increased expression of TGFB1 proteinixntetrathiomolybdate inhibits the reaction [Bleomycin results in increased expression of CCL2 mRNA]ixntetrathiomolybdate inhibits the reaction [Bleomycin results in increased expression of CCL2 protein]ixntetrathiomolybdate has a real or putative therapeutic role towards Pulmonary FibrosisixnBleomycin results in increased expression of CCL2 mRNAixnBleomycin plays a role in or acts as a marker for Pulmonary Fibrosisixntetrathiomolybdate inhibits the reaction [Bleomycin results in increased expression of TNF mRNA]ixntetrathiomolybdate inhibits the reaction [Bleomycin results in increased expression of TGFB1 protein]ixnBleomycin results in increased expression of CCL2 protein20638373title0Cajanol, a novel anticancer agent from Pigeonpea [Cajanus cajan (L.) Millsp.] roots, induces apoptosis in human breast cancer cells through a ROS-mediated mitochondrial pathway.abstract178Cajanol (5-hydroxy-3-(4-hydroxy-2-methoxyphenyl)-7-methoxychroman-4-one) is an isoflavanone from Pigeonpea [Cajanus cajan (L.) Millsp.] roots. As the most effective phytoalexin in pigeonpea, the cytotoxic activity of cajanol towards cancer cells has not been report as yet. In the present study, the anticancer activity of cajanol towards MCF-7 human breast cancer cells was investigated. In order to explore the underlying mechanism of cell growth inhibition of cajanol, cell cycle distribution, DNA fragmentation assay and morphological assessment of nuclear change, ROS generation, mitochondrial membrane potential (DeltaPsim) disruption, and expression of caspase-3 and caspase-9, Bax, Bcl-2, PARP and cytochrome c were measured in MCF-7 cells. Cajanol inhibited the growth of MCF-7 cells in a time and dose-dependent manner. The IC(50) value was 54.05 microM after 72 h treatment, 58.32 microM after 48 h; and 83.42 microM after 24h. Cajanol arrested the cell cycle in the G2/M phase and induced apoptosis via a ROS-mediated mitochondria-dependent pathway. Western blot analysis showed that cajanol inhibited Bcl-2 expression and induced Bax expression to desintegrate the outer mitochondrial membrane and causing cytochrome c release. Mitochondrial cytochrome c release was associated with the activation of caspase-9 and caspase-3 cascade, and active-caspase-3 was involved in PARP cleavage. All of these signal transduction pathways are involved in initiating apoptosis. To the best of our knowledge, this is the first report demonstrating the cytotoxic activity of cajanol towards cancer cells in vitro.chemCAJANOLdiseaseBREAST NEOPLASMSgeneCASP9geneBCL2geneBAXgeneCYCSgeneCASP3action termexpressionaction termlocalizationaction termcotreatmentaction termactivityixn[[[cajanol results in decreased expression of BCL2 protein] co-treated with [cajanol results in increased expression of BAX protein]] affects the localization of CYCS protein] which results in increased activity of CASP9 proteinixncajanol results in decreased expression of BCL2 proteinixncajanol results in increased activity of CASP3 proteinixncajanol results in increased expression of BAX proteinixn[[cajanol results in decreased expression of BCL2 protein] co-treated with [cajanol results in increased expression of BAX protein]] affects the localization of CYCS proteinixncajanol affects the localization of CYCS proteinixncajanol has a real or putative therapeutic role towards Breast Neoplasmsixncajanol results in increased activity of CASP9 proteinixn[[[cajanol results in decreased expression of BCL2 protein] co-treated with [cajanol results in increased expression of BAX protein]] affects the localization of CYCS protein] which results in increased activity of CASP3 protein19207477title0Effects of quercetin on gene and protein expression of NOX and NOS after myocardial ischemia and reperfusion in rabbit.abstract120Previous studies have suggested that reactive oxygen species (ROS), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) are involved in the pathophysiology of myocardial ischemia-reperfusion injury (MIRI). The NOX family of NADPH oxidases share the capacity to generate superoxide and ROS. Several studies have demonstrated that quercetin possesses a protective effect against MIRI. Our aim is to investigate the effects of quercetin on NOX2, eNOS, and iNOS after MIRI in rabbits. New Zealand rabbits were subjected to 30 min of myocardial ischemia followed by 12 h of reperfusion. They were then randomly assigned to four experimental groups: control, I/R (ischemia/reperfusion), quercetin (Que), I/R + Que. Gene and protein expression of NOX2, eNOS, and iNOS were compared. Both in real-time PCR and in the Western blotting studies, myocardial ischemia-reperfusion-induced NOX2 and iNOS expression were enhanced (P < 0.01) but eNOS mRNA and protein expression in I/R hearts were not significantly different from those in control (P < 0.01). Administration of quercetin reduced NOX2, eNOS, and iNOS mRNA and protein expression both in control and in I/R heart (P < 0.01). Gene and protein expression of NOX2 and iNOS were increased after MIRI. Quercetin not only inhibited myocardial ischemia-reperfusion-induced NOX2 and iNOS mRNA and protein expression but also inhibited eNOS mRNA and protein expression.chemQUERCETINdiseaseMYOCARDIAL REPERFUSION INJURYgeneNOS2geneNOS3geneCYBBaction termexpressionixnCYBB plays a role in or acts as a marker for Myocardial Reperfusion InjuryixnNOS2 plays a role in or acts as a marker for Myocardial Reperfusion InjuryixnQuercetin has a real or putative therapeutic role towards Myocardial Reperfusion InjuryixnQuercetin results in decreased expression of CYBB mRNAixnQuercetin results in decreased expression of NOS3 mRNAixnQuercetin results in decreased expression of NOS2 mRNAixnQuercetin results in decreased expression of CYBB proteinixnQuercetin results in decreased expression of NOS3 proteinixnQuercetin results in decreased expression of NOS2 protein20137537title0[Effects of losartan and simvastatin on collagen content, myocardial expression of MMP-2 mRNA, MMP-9 mRNA and TIMP-1 mRNA, TIMP-2 mRNA in pressure overload rat hearts].abstract169OBJECTIVE: To investigate the effects of simvastatin(Sim) and losartan(Los) on cardiac fibrosis and myocardial expression of MMP-2 mRNA, MMP-9 mRNA and TIMP-1 mRNA, TIMP-2 mRNA in pressure overloaded rat hearts.
METHODS: The pressure overload model was induced by descending aortic constriction (DAC) in rats. SD rats were randomized into 6 groups (n = 20 each): normol control group, control sham group, DAC group, Los group (DAC + Los, 5 mg/kg), Sim group (DAC + Sim, 2 mg/kg), Los + Sim group (DAC + Los + Sim, Los 5 mg/kg, Sim 2 mg/kg). Water, Los or Sim drug was administrated by gavage daily beginning from day 5 after operation for 30 days. Collagen was measured on Masson stained myocardial sections, and the level of MMP-2 mRNA, MMP-9 mRNA and TIMP-1 mRNA, TIMP-2 mRNA in left ventricle were detected by RT-PCR.
RESULTS: Collagen volume fraction (CVF) in DAC group was significantly higher than the normal control and sham groups (P < 0.01) which could be significantly reduced by Los and Sim (P < 0.05), especially in DAC + Los + Sim group (P < 0.01). The levels of myocardial MMP-2 mRNA, MMP-9 mRNA and TIMP-1 mRNA, TIMP-2 mRNA were also significantly higher in DAC group than in normal control and sham groups (P < 0.01). Treatment Sim and Los alone and especially in combination significantly decreased the TIMP-1 mRNA, TIMP-2 mRNA expressions (P < 0.01) while MMP-2 mRNA, MMP-9 mRNA levels remained unchanged (P > 0.05).
CONCLUSION: Upregulation of myocardial MMP-2 mRNA, MMP-9 mRNA and TIMP-1 mRNA, TIMP-2 mRNA expressions might contribute to myocardial fibrosis in this model, Sim and Los significantly inhibited myocardial fibrosis possibly by downregulating myocardial TIMP-1 mRNA, TIMP-2 mRNA expressions in this model.chemLOSARTANchemSIMVASTATINdiseaseFIBROSISgeneTIMP1geneTIMP2action termexpressionaction termreactionixnLosartan results in decreased expression of TIMP1 mRNAixnLosartan results in decreased expression of TIMP2 mRNAixnSimvastatin results in decreased expression of TIMP1 mRNAixnSimvastatin inhibits the reaction [Losartan results in decreased expression of TIMP2 mRNA]ixnSimvastatin has a real or putative therapeutic role towards FibrosisixnSimvastatin inhibits the reaction [Losartan results in decreased expression of TIMP1 mRNA]ixnSimvastatin results in decreased expression of TIMP2 mRNAixnLosartan inhibits the reaction [Simvastatin results in decreased expression of TIMP1 mRNA]ixnLosartan has a real or putative therapeutic role towards FibrosisixnLosartan inhibits the reaction [Simvastatin results in decreased expression of TIMP2 mRNA]16868541title0Phellinus linteus sensitises apoptosis induced by doxorubicin in prostate cancer.abstract82It has been demonstrated that the Phellinus linteus (PL) mushroom, which mainly consists of polysaccharides, possesses antitumour activity. The mechanisms of PL against malignant growth remain unknown. The anticancer drug doxorubicin (Dox) has been shown to induce apoptosis via initiating a caspase cascade. In this investigation, we tested the effect of PL on Dox-induced apoptosis in prostate cancer LNCaP cells. We showed that PL or Dox, at relatively low doses, does not induce apoptosis in the cells. However, combination treatment with low doses of PL and Dox results in a synergistic effect on the induction of apoptosis. In this apoptotic process, caspases 8, 3 and BID are cleaved, and the addition of caspase inhibitor z-VADfmk completely blocks apoptosis. In addition, JNK is activated in response to PL or the combination treatment in LNCaP cells. The suppression of JNK partially inhibits the induction of apoptosis elicited by the co-treatment. These findings indicate that PL has a synergistic effect with Dox to activate caspases in prostate cancer LNCaP cells. Our study also suggests that PL has therapeutic potential to augment the magnitude of apoptosis induced by antiprostate cancer drugs.chemDOXORUBICINchemPHELLINUS LINTEUS EXTRACTdiseasePROSTATIC NEOPLASMSgeneMAPK8geneCASP8geneCASP3geneCFLARgeneCYCSgeneBIDaction termexpressionaction termlocalizationaction termcotreatmentaction termphosphorylationaction termcleavageaction termactivityixnDoxorubicin has a real or putative therapeutic role towards Prostatic NeoplasmsixnPhellinus linteus extract has a real or putative therapeutic role towards Prostatic Neoplasmsixn[Doxorubicin co-treated with Phellinus linteus extract] results in increased cleavage of and results in increased activity of CASP3 proteinixn[Doxorubicin co-treated with Phellinus linteus extract] results in increased cleavage of and results in increased activity of CASP8 proteinixn[Doxorubicin co-treated with Phellinus linteus extract] results in increased cleavage of BID proteinixn[Doxorubicin co-treated with Phellinus linteus extract] affects the localization of CYCS proteinixn[Doxorubicin co-treated with Phellinus linteus extract] results in increased expression of and results in increased phosphorylation of and results in increased activity of MAPK8 proteinixnPhellinus linteus extract results in increased expression of and results in increased phosphorylation of and results in increased activity of MAPK8 proteinixnPhellinus linteus extract results in decreased expression of CFLAR protein alternative form20064788title0Polychlorinated biphenyls disrupt blood-brain barrier integrity and promote brain metastasis formation.abstract104BACKGROUND: Polychlorinated biphenyls (PCBs) comprise a ubiquitous class of toxic substances associated with carcinogenic and tumor-promoting effects as well as neurotoxic properties in the brain. However, the effects of PCBs on the development of tumor metastases are not fully understood.
OBJECTIVE: We evaluated the hypothesis that exposure to individual PCB congeners can facilitate the development of brain metastases in immunocompetent mice via the disruption of the integrity of the blood-brain barrier (BBB).
METHODS: C57/Bl6 mice were exposed to individual PCBs by oral gavage, and 48 hr later they were injected with luciferase-labeled K1735 M2 melanoma cells into the internal carotid artery. The development of metastatic nodules was monitored by bioluminescent imaging. In addition, we evaluated the functional permeability of the BBB by measuring permeability of sodium fluorescein across the brain microvessels. Expression and colocalization of tight junction (TJ) proteins were studied by Western blotting and immunofluorescence microscopy.
RESULTS: Oral administration of coplanar PCB126, mono-ortho-substituted PCB118, and non-coplanar PCB153 (each at 150 micromol/kg body weight) differentially altered expression of the TJ proteins claudin-5, occludin, and zonula occludens-1 in brain capillaries. These alterations were associated with increased permeability of the BBB. Most importantly, exposure to individual PCB congeners enhanced the rate of formation and progression of brain metastases of luciferase-tagged melanoma cells.
CONCLUSIONS: Our results show for the first time that exposure to individual PCBs can facilitate the formation of bloodborne metastases via alterations of the integrity of the brain capillary endothelium.chem3,4,5,3',4'-PENTACHLOROBIPHENYLchem2,4,5,2',4',5'-HEXACHLOROBIPHENYLchem2,3',4,4',5-PENTACHLOROBIPHENYLdiseaseNEOPLASM METASTASISgeneOCLNgeneTJP1geneCLDN5action termreactionaction termexpressionaction termbindingixn2,4,5,2',4',5'-hexachlorobiphenyl results in increased expression of TJP1 proteinixn3,4,5,3',4'-pentachlorobiphenyl plays a role in or acts as a marker for Neoplasm Metastasisixn3,4,5,3',4'-pentachlorobiphenyl promotes the reaction [TJP1 protein binds to OCLN protein]ixn2,3',4,4',5-pentachlorobiphenyl affects the reaction [TJP1 protein binds to OCLN protein]ixn2,3',4,4',5-pentachlorobiphenyl plays a role in or acts as a marker for Neoplasm Metastasisixn2,4,5,2',4',5'-hexachlorobiphenyl results in decreased expression of CLDN5 proteinixn2,3',4,4',5-pentachlorobiphenyl results in increased expression of TJP1 proteinixn2,4,5,2',4',5'-hexachlorobiphenyl plays a role in or acts as a marker for Neoplasm Metastasisixn2,3',4,4',5-pentachlorobiphenyl results in decreased expression of CLDN5 proteinixn2,4,5,2',4',5'-hexachlorobiphenyl promotes the reaction [TJP1 protein binds to OCLN protein]12602925title0Cell proliferation, apoptosis, and expression of cyclin D1 and cyclin E as potential biomarkers in tamoxifen-treated mammary tumors.abstract133Tamoxifen has been widely used for treatment, and more recently, for the prevention of breast cancer. Since breast carcinomas are composed of heterogeneous populations of estrogen receptor-positive (ER+) cells, we hypothesized that tamoxifen may suppress tumor growth by differentially affecting cell proliferation and apoptosis. ER+ mammary tumors were induced in Sprague-Dawley rats by N-methyl-N-nitrosourea (MNU) and when they became palpable, the animals were treated for 5, 10, or 20 days with tamoxifen, 1.0 mg/kg body weight. Tamoxifen induced a time-dependent decrease in proliferating (BrdU-labeled) cells, arrested the cells in G1/0 phase, and differentially decreased the cyclin E and cyclin D1 expression at mRNA and protein levels. In the same tumors, apoptotic cells increased during the first 10 days of treatment, but their number remained unchanged with extension of the treatment to 20 days. Thus, we provide data that tamoxifen may differentially affect cell proliferation and apoptosis in mammary tumors and that the expression levels of cyclin D1 and cyclin E might also be considered potential intermediate biomarkers of response of mammary tumors to tamoxifen and possibly to other selective estrogen receptor modulators (SERMs).chemMETHYLNITROSOUREAchemTAMOXIFENdiseaseBREAST NEOPLASMSgeneCCNE1genePCNAgeneCCND1action termexpressionixnMethylnitrosourea plays a role in or acts as a marker for Breast NeoplasmsixnTamoxifen has a real or putative therapeutic role towards Breast NeoplasmsixnTamoxifen results in decreased expression of CCND1 proteinixnTamoxifen results in decreased expression of CCNE1 proteinixnTamoxifen results in decreased expression of CCND1 mRNAixnTamoxifen results in decreased expression of CCNE1 mRNAixnTamoxifen results in decreased expression of PCNA mRNA19656910title0Rosiglitazone prevents sirolimus-induced hypomagnesemia, hypokalemia, and downregulation of NKCC2 protein expression.abstract118Sirolimus, an antiproliferative immunosuppressant, induces hypomagnesemia and hypokalemia. Rosiglitazone activates renal sodium- and water-reabsorptive pathways. We evaluated whether sirolimus induces renal wasting of magnesium and potassium, attempting to identify the tubule segments in which this occurs. We tested the hypothesis that reduced expression of the cotransporter NKCC2 forms the molecular basis of this effect and evaluated the possible association between increased urinary excretion of magnesium and renal expression of the epithelial Mg2+ channel TRPM6. We then analyzed whether rosiglitazone attenuates these sirolimus-induced tubular effects. Wistar rats were treated for 14 days with sirolimus (3 mg/kg body wt in drinking water), with or without rosiglitazone (92 mg/kg body wt in food). Protein abundance of NKCC2, aquaporin-2 (AQP2), and TRPM6 was assessed using immunoblotting. Sirolimus-treated animals presented no change in glomerular filtration rate, although there were marked decreases in plasma potassium and magnesium. Sirolimus treatment reduced expression of NKCC2, and this was accompanied by greater urinary excretion of sodium, potassium, and magnesium. In sirolimus-treated animals, AQP2 expression was reduced. Expression of TRPM6 was increased, which might represent a direct stimulatory effect of sirolimus or a compensatory response. The finding that rosiglitazone prevented or attenuated all sirolimus-induced renal tubular defects has potential clinical implications.chemROSIGLITAZONEchemSIROLIMUSdiseaseHYPOKALEMIAdiseaseMAGNESIUM DEFICIENCYgeneTRPM6geneSLC12A1geneAQP2action termreactionaction termexpressionixnSirolimus plays a role in or acts as a marker for Magnesium DeficiencyixnSirolimus results in decreased expression of AQP2 proteinixnSirolimus results in decreased expression of SLC12A1 proteinixnSirolimus results in increased expression of TRPM6 proteinixnrosiglitazone inhibits the reaction [Sirolimus results in decreased expression of SLC12A1 protein]ixnrosiglitazone has a real or putative therapeutic role towards Magnesium Deficiencyixnrosiglitazone has a real or putative therapeutic role towards HypokalemiaixnSirolimus plays a role in or acts as a marker for Hypokalemiaixnrosiglitazone inhibits the reaction [Sirolimus results in increased expression of TRPM6 protein]ixnrosiglitazone inhibits the reaction [Sirolimus results in decreased expression of AQP2 protein]19763542title0Effects of 4-pyridine aldoxime on nerve agent-inhibited acetylcholinesterase activity in guinea pigs.abstract102Methoxime (MMB-4) is a leading candidate oxime acetylcholinesterase (AChE) reactivator to replace pralidoxime (2-PAM) for therapeutic treatment of nerve agent intoxication. 4-Pyridine aldoxime (4-PA) is a synthetic starting material, a breakdown product, and a probable metabolite of MMB-4. There is a possibility that 4-PA may adversely interact with the nerve agent, thereby affecting nerve agent toxicity and biological AChE activity. This study evaluated the effects of 4-PA on sarin (GB)-, cyclosarin (GF)-, and VX-induced toxicity and AChE activity in blood, brain, and peripheral tissues of guinea pigs. Animals were pretreated with atropine methyl nitrate (1.0 mg/kg, im) 15 min prior to subcutaneous administration with 1.0 x LD(50) of GB, GF, or VX and then treated 15 min after the administration of nerve agents with 4-PA (3.5, 7.0, or 14.0 mg/kg, im). The dose-response effects of 4-PA alone were also examined. Toxic signs and lethality were monitored, blood and tissues were collected, and AChE activities were determined at 60 min after nerve agent administration. Under the condition of this study, all animals exposed to nerve agents exhibited some degree of toxic signs such as salivation, lacrimation, rhinorrhea, and convulsions. 4-PA at the three doses tested neither induced toxic signs nor altered the toxicity of GB, GF, or VX at the 1.0 x LD(50) exposure dose. Additionally, it did not modify the AChE activity in blood, brain, and peripheral tissues by itself or affect the AChE activity inhibited by a 1.0 x LD(50) dose of these three nerve agents in guinea pigs.chemVXchemSARINchemCYCLOHEXYL METHYLPHOSPHONOFLUORIDATEdiseaseNEUROTOXICITY SYNDROMESdiseaseSEIZURESgeneACHEaction termactivityixncyclohexyl methylphosphonofluoridate plays a role in or acts as a marker for Neurotoxicity SyndromesixnVX plays a role in or acts as a marker for Neurotoxicity SyndromesixnSarin plays a role in or acts as a marker for SeizuresixnSarin plays a role in or acts as a marker for Neurotoxicity Syndromesixncyclohexyl methylphosphonofluoridate plays a role in or acts as a marker for SeizuresixnVX plays a role in or acts as a marker for SeizuresixnSarin results in decreased activity of ACHE proteinixncyclohexyl methylphosphonofluoridate results in decreased activity of ACHE proteinixnVX results in decreased activity of ACHE protein20624417title0Coadministration of huperzine A and ligustrazine phosphate effectively reverses scopolamine-induced amnesia in rats.abstract117In the present study, whether coadministration of huperzine A (HA) and ligustrazine phosphate (LP) could effectively improve the memory deficits in association with ameliorating cholinergic impairment and oxidative stress in the scopolamine-induced amnesia rats was assessed. The effects of treatment with Coa [HA (0.14 mg/kg, i.g.) and LP (110 mg/kg, i.g.)] on amnesia were investigated in Morris water maze. Furthermore, the effects on the activities of acetylcholinesterase (AChE) and antioxidant enzymes within the cerebral cortex and hippocampus were evaluated, and the lipid peroxidation product malondialdehyde (MDA) was also analyzed. As a result, coadministration of HA and LP for 10 consecutive days could markedly reverse the scopolamine-induced learning and memory impairment determined by the Morris water maze test. Moreover, AChE activity was significantly inhibited, and superoxide dismutases (SOD) and glutathione peroxidase (GSH-Px) activities were significantly increased with a remarkable reduction in the level of MDA. In conclusion, coadministration of HA and LP effectively prevented cholinergic impairment and oxidative damage, thereby resulting in improvement of spatial learning memory in rats induced by scopolamine. The results suggested that coadministration of HA and LP might offer a novel poly-therapeutic drug regimen for preventing Alzheimer''s disease (AD).chemSCOPOLAMINE HYDROBROMIDEchemMALONDIALDEHYDEchemHUPERZINE AchemTETRAMETHYLPYRAZINEdiseaseMEMORY DISORDERSdiseaseLEARNING DISORDERSgeneACHEaction termcotreatmentaction termactivityixnMalondialdehyde plays a role in or acts as a marker for Learning Disordersixnhuperzine A has a real or putative therapeutic role towards Memory Disordersixnhuperzine A has a real or putative therapeutic role towards Learning Disordersixntetramethylpyrazine has a real or putative therapeutic role towards Learning DisordersixnScopolamine Hydrobromide plays a role in or acts as a marker for Memory Disordersixntetramethylpyrazine has a real or putative therapeutic role towards Memory Disordersixn[huperzine A co-treated with tetramethylpyrazine] results in decreased activity of ACHE proteinixnMalondialdehyde plays a role in or acts as a marker for Memory DisordersixnScopolamine Hydrobromide plays a role in or acts as a marker for Learning Disorders19705549title0A study of brain insulin receptors, AChE activity and oxidative stress in rat model of ICV STZ induced dementia.abstract113In the present study, role of brain insulin receptors (IRs) in memory functions and its correlation with acetylcholinesterase (AChE) activity and oxidative stress in different brain regions were investigated in intracerebroventricular (ICV) streptozotocin (STZ) induced dementia model. Rats were treated with STZ (3 mg/kg, ICV) on day 1 and 3. Donepezil (5 mg/kg po) and melatonin (20 mg/kg ip) were administered in pre- and post-treatment schedules. Morris water maze test was done on day 14 and animals were sacrificed on day 21 from 1st STZ injection. Memory deficit was found in STZ group as indicated by no significant decrease in latency time antagonized by donepezil and melatonin. IR protein level was found significantly increased in trained group as compared to control, whereas STZ decreased IR level significantly as compared to trained rats in hippocampus which indicates that IR is associated with memory functions. STZ induced decrease in IR was reversed by melatonin but not by donepezil. Melatonin per se did not show any significant change in IR level as compared to control. AChE activity (DS and SS fraction) was found to be increased in hippocampus in STZ group as compared to trained which was inhibited by donepezil and melatonin. Increase in MDA level and decrease in GSH level were obtained in STZ group indicating oxidative stress, which was attenuated by donepezil and melatonin. Effectiveness of antioxidant, melatonin but not of anti-cholinesterase, donepezil against STZ induced changes in IR indicates that IR is more affected with oxidative stress than cholinergic changes.chemSTREPTOZOCINchemDONEPEZILchemMELATONINdiseaseDEMENTIAdiseaseMEMORY DISORDERSdiseaseDISEASE MODELS, ANIMALgeneINSRgeneACHEaction termexpressionaction termreactionaction termactivityixnMelatonin has a real or putative therapeutic role towards Memory DisordersixnStreptozocin plays a role in or acts as a marker for DementiaixnMelatonin inhibits the reaction [Streptozocin results in decreased expression of INSR protein]ixndonepezil inhibits the reaction [Streptozocin results in increased activity of ACHE protein]ixnStreptozocin plays a role in or acts as a marker for Disease Models, AnimalixnStreptozocin plays a role in or acts as a marker for Memory DisordersixnStreptozocin results in decreased expression of INSR proteinixnStreptozocin results in increased activity of ACHE proteinixnMelatonin inhibits the reaction [Streptozocin results in increased activity of ACHE protein]ixndonepezil has a real or putative therapeutic role towards Memory Disorders19443634title0Nck proteins maintain the adult glomerular filtration barrier.abstract63Within the glomerulus, the scaffolding protein nephrin bridges the actin-rich foot processes that extend from adjacent podocytes to form the slit diaphragm. Mutations affecting a number of slit diaphragm proteins, including nephrin, cause glomerular disease through rearrangement of the actin cytoskeleton and disruption of the filtration barrier. We recently established that the Nck family of Src homology 2 (SH2)/SH3 cytoskeletal adaptor proteins can mediate nephrin-dependent actin reorganization. Formation of foot processes requires expression of Nck in developing podocytes, but it is unknown whether Nck maintains podocyte structure and function throughout life. Here, we used an inducible transgenic strategy to delete Nck expression in adult mouse podocytes and found that loss of Nck expression rapidly led to proteinuria, glomerulosclerosis, and altered morphology of foot processes. We also found that podocyte injury reduced phosphorylation of nephrin in adult kidneys. These data suggest that Nck is required to maintain adult podocytes and that phosphotyrosine-based interactions with nephrin may occur in foot processes of resting, mature podocytes.chemPUROMYCIN AMINONUCLEOSIDEdiseaseNEPHROSISdiseaseNEPHROTIC SYNDROMEdiseaseALBUMINURIAdiseasePROTEINURIAgeneNCK1geneNPHS1geneNCK2action termphosphorylationixnPuromycin Aminonucleoside plays a role in or acts as a marker for NephrosisixnNCK2 plays a role in or acts as a marker for Nephrotic SyndromeixnNCK2 plays a role in or acts as a marker for ProteinuriaixnNCK1 plays a role in or acts as a marker for Nephrotic SyndromeixnNCK1 plays a role in or acts as a marker for ProteinuriaixnNCK1 plays a role in or acts as a marker for AlbuminuriaixnPuromycin Aminonucleoside results in decreased phosphorylation of NPHS1 proteinixnNCK2 plays a role in or acts as a marker for AlbuminuriaixnPuromycin Aminonucleoside plays a role in or acts as a marker for Proteinuria20674374title0New synthetic flavone derivatives induce apoptosis of hepatocarcinoma cells.abstract77Natural flavonoids have broad biological activity, including anticancer. In this study, a series of novel flavone derivatives were synthesized with the substitutions of chlorine, isopropyl, methoxy, and nitro groups on the benzene ring of flavone skeleton to develop effective anticancer agents. Antiproliferative assays showed that the synthesized chemicals possess notable activity against hepatocarcinoma cells (HepG-2); in particular, the compound 6f with chlorine and dimethoxy modifications at the two benzene rings showed an IC(50) at 1.1 microM to HepG-2. The 6f also displayed marked anticancer activity towards a panel of cancer cells, including nasopharyngeal carcinoma cells (CNE-2 and CNE-1), breast adenocarcinoma cell (MCF-7), and epithelial carcinoma cells (Hela). Exposing HepG-2 cells to compound 6f at 10 microM induced chromatin condensation, nuclear disassembly, and DNA fragmentation. In 6f-treated HepG-2 cells, the sub-G(0) population was remarkably increased; and in these cells, both caspase-8 and caspase-9 activity was significantly increased, which in turn activated caspase-3. In addition, proapoptotic Bax was upregulated by compound 6f while the antiapoptotic Bcl-2 was downregulated. Taken together, our data suggest that the new flavonoid derivative 6f triggers apoptosis through both death-receptor and mitochondria-dependent intrinsic pathways, being a potent therapeutic agent against hepatocarcinoma.chemFLAVONESdiseaseBREAST NEOPLASMSdiseaseCARCINOMA, HEPATOCELLULARdiseaseNASOPHARYNGEAL CARCINOMAdiseaseCARCINOMAgeneBCL2geneCASP8geneCASP9geneCASP3geneBAXaction termexpressionaction termactivityixnFlavones has a real or putative therapeutic role towards Breast NeoplasmsixnFlavones analog results in increased activity of CASP8 proteinixnFlavones analog results in increased activity of CASP3 proteinixnFlavones analog results in increased expression of BAX mRNAixnFlavones has a real or putative therapeutic role towards Carcinoma, HepatocellularixnFlavones analog results in increased activity of CASP9 proteinixnFlavones analog results in increased expression of BCL2 mRNAixnFlavones has a real or putative therapeutic role towards Nasopharyngeal carcinomaixnFlavones has a real or putative therapeutic role towards Carcinoma19413659title0Uroprotective effects of curcumin in cyclophosphamide-induced haemorrhagic cystitis paradigm.abstract94The possible uroprotective effects of curcumin have been addressed in the current study. Haemorrhagic cystitis was induced by challenging male Swiss albino rats with a single dose of cyclophosphamide (150 mg/kg, i.p.). Curcumin (200 mg/kg, i.p.) was administered for 10 consecutive days followed by a single dose of cyclophosphamide. Haemorrhagic cystitis was well characterized morphologically and biochemically. The hallmark of this toxicity was marked congestion, oedema and extravasation in rat urinary bladder, as well as a marked desquamative damage to the urothelium and severe inflammation in the lamina propria. Leucocytic infiltration was also observed and determined by histopathological examination. Serum level of tumour necrosis factor-alpha was notably elevated associated with apparent hypokalaemia and hyponatraemia. Bladder contents of adenosine triphosphate, reduced glutathione and glutathione-S-transferase activity were markedly reduced. Malondialdehyde level, myeloperoxidase activity and urinary nitrite-nitrate levels, expressed as nitric oxide, were dramatically increased. Prior administration of curcumin ahead of cyclophosphamide challenge improved all the biochemical and histologic alterations induced by the cytotoxic drug. Based on these broad findings, it could be concluded that curcumin has proven uroprotective efficacy in this cyclophosphamide haemorrhagic cystitis model, possibly through modulating the release of inflammatory endocoids, namely tumour necrosis factor-alpha and nitric oxide, improving the energy status and restoring the oxidant/antioxidant balance.chemCYCLOPHOSPHAMIDEchemCURCUMINdiseaseINFLAMMATIONdiseaseEDEMAdiseaseCYSTITISdiseaseHEMORRHAGEgeneTNFaction termreactionaction termexpressionixnCyclophosphamide plays a role in or acts as a marker for EdemaixnCurcumin has a real or putative therapeutic role towards EdemaixnCyclophosphamide plays a role in or acts as a marker for InflammationixnCyclophosphamide plays a role in or acts as a marker for CystitisixnCyclophosphamide results in increased expression of TNF proteinixnCyclophosphamide plays a role in or acts as a marker for HemorrhageixnCurcumin has a real or putative therapeutic role towards InflammationixnCurcumin has a real or putative therapeutic role towards CystitisixnCurcumin has a real or putative therapeutic role towards HemorrhageixnCurcumin inhibits the reaction [Cyclophosphamide results in increased expression of TNF protein]19339610title0Neuropeptide S reinstates cocaine-seeking behavior and increases locomotor activity through corticotropin-releasing factor receptor 1 in mice.abstract143Neuropeptide S (NPS) is a recently discovered neuropeptide that increases arousal and wakefulness while decreasing anxiety-like behavior. Here, we used a self-administration paradigm to demonstrate that intracerebroventricular infusion of NPS reinstates extinguished cocaine-seeking behavior in a dose-dependent manner in mice. The highest dose of NPS (0.45 nM) increased active lever pressing in the absence of cocaine to levels that were equivalent to those observed during self-administration. In addition, we examined the role of the corticotropin-releasing factor receptor 1 (CRF(1)) in this behavior as well as locomotor stimulation and anxiolysis. CRF(1) knock-out mice did not respond to either the locomotor stimulant or cocaine reinstatement effects of NPS, but still responded to its anxiolytic effect. The CRF(1) antagonist antalarmin also blocked the increase in active lever responding in the reinstatement model and the locomotor activating properties of NPS without affecting its anxiolytic actions. Our results suggest that NPS receptors may be an important target for drug abuse research and treatment and that CRF(1) mediates the cocaine-seeking and locomotor stimulant effects of NPS, but not its effects on anxiety-like behavior.chemANTALARMINchemCOCAINEdiseaseANXIETY DISORDERSdiseaseCOCAINE-RELATED DISORDERSdiseaseHYPERKINESISgeneNPSgeneCRHR1action termbindingaction termactivityixnCRHR1 plays a role in or acts as a marker for HyperkinesisixnNPS has a real or putative therapeutic role towards Anxiety DisordersixnCRHR1 plays a role in or acts as a marker for Cocaine-Related Disordersixnantalarmin has a real or putative therapeutic role towards Cocaine-Related DisordersixnNPS plays a role in or acts as a marker for Hyperkinesisixnantalarmin binds to and results in decreased activity of CRHR1 proteinixnantalarmin has a real or putative therapeutic role towards HyperkinesisixnNPS plays a role in or acts as a marker for Cocaine-Related DisordersixnCocaine plays a role in or acts as a marker for Cocaine-Related Disorders22164206title0Nicotinamide inhibits alkylating agent-induced apoptotic neurodegeneration in the developing rat brain.abstract104BACKGROUND: Exposure to the chemotherapeutic alkylating agent thiotepa during brain development leads to neurological complications arising from neurodegeneration and irreversible damage to the developing central nerve system (CNS). Administration of single dose of thiotepa in 7-d postnatal (P7) rat triggers activation of apoptotic cascade and widespread neuronal death. The present study was aimed to elucidate whether nicotinamide may prevent thiotepa-induced neurodegeneration in the developing rat brain.
METHODOLOGY/PRINCIPAL FINDINGS: Neuronal cell death induced by thiotepa was associated with the induction of Bax, release of cytochrome-c from mitochondria into the cytosol, activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP-1). Post-treatment of developing rats with nicotinamide suppressed thiotepa-induced upregulation of Bax, reduced cytochrome-c release into the cytosol and reduced expression of activated caspase-3 and cleavage of PARP-1. Cresyl violet staining showed numerous dead cells in the cortex hippocampus and thalamus; post-treatment with nicotinamide reduced the number of dead cells in these brain regions. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) and immunohistochemical analysis of caspase-3 show that thiotepa-induced cell death is apoptotic and that it is inhibited by nicotinamide treatment.
CONCLUSION: Nicotinamide (Nic) treatment with thiotepa significantly improved neuronal survival and alleviated neuronal cell death in the developing rat. These data demonstrate that nicotinamide shows promise as a therapeutic and neuroprotective agent for the treatment of neurodegenerative disorders in newborns and infants.chemNIACINAMIDEchemTHIOTEPAdiseaseNEURODEGENERATIVE DISEASESgenePARP1geneBAXgeneCASP3action termreactionaction termexpressionaction termcleavageaction termactivityixnThiotepa results in increased expression of BAX mRNAixnNiacinamide inhibits the reaction [Thiotepa results in increased expression of BAX mRNA]ixnThiotepa results in increased expression of BAX proteinixnNiacinamide inhibits the reaction [Thiotepa results in increased expression of BAX protein]ixnNiacinamide inhibits the reaction [Thiotepa results in increased activity of CASP3 protein]ixnThiotepa results in increased activity of CASP3 proteinixnNiacinamide inhibits the reaction [Thiotepa results in increased cleavage of PARP1 protein]ixnThiotepa results in increased cleavage of PARP1 proteinixnThiotepa plays a role in or acts as a marker for Neurodegenerative DiseasesixnNiacinamide has a real or putative therapeutic role towards Neurodegenerative Diseases20056921title0FTY720 stimulates 27-hydroxycholesterol production and confers atheroprotective effects in human primary macrophages.abstract118RATIONALE: The synthetic sphingosine analog FTY720 is undergoing clinical trials as an immunomodulatory compound, acting primarily via sphingosine 1-phosphate receptor activation. Sphingolipid and cholesterol homeostasis are closely connected but whether FTY720 affects atherogenesis in humans is not known.
OBJECTIVE: We examined the effects of FTY720 on the processing of scavenged lipoprotein cholesterol in human primary monocyte-derived macrophages.
METHODS AND RESULTS: FTY720 did not affect cholesterol uptake but inhibited its delivery to the endoplasmic reticulum, reducing cellular free cholesterol cytotoxicity. This was accompanied by increased levels of Niemann-Pick C1 protein (NPC1) and ATP-binding cassette transporter (ABC)A1 proteins and increased efflux of endosomal cholesterol to apolipoprotein A-I. These effects were not dependent on sphingosine 1-phosphate receptor activation. Instead, FTY720 stimulated the production of 27-hydroxycholesterol, an endogenous ligand of the liver X receptor, leading to liver X receptor-induced upregulation of ABCA1. Fluorescently labeled FTY720 was targeted to late endosomes, and the FTY720-induced upregulation of ABCA1 was NPC1-dependent, but the endosomal exit of FTY720 itself was not.
CONCLUSIONS: We conclude that FTY720 decreases cholesterol toxicity in primary human macrophages by reducing the delivery of scavenged lipoprotein cholesterol to the endoplasmic reticulum and facilitating its release to physiological extracellular acceptors. Furthermore, FTY720 stimulates 27-hydroxycholesterol production, providing an explanation for the atheroprotective effects and identifying a novel mechanism by which FTY720 modulates signaling.chemTO-901317chemUVI 3003chemFINGOLIMODchem27-HYDROXYCHOLESTEROLchemCHOLESTEROLdiseaseATHEROSCLEROSISgeneABCA1geneNPC1geneAPOA1action termreactionaction termexpressionaction termsecretionaction termabundanceixnfingolimod has a real or putative therapeutic role towards Atherosclerosisixnfingolimod promotes the reaction [APOA1 protein results in increased secretion of Cholesterol]ixnUVI 3003 inhibits the reaction [fingolimod results in increased expression of ABCA1 protein]ixnfingolimod results in increased expression of NPC1 proteinixnfingolimod results in increased expression of ABCA1 mRNAixnfingolimod results in increased expression of ABCA1 proteinixnAPOA1 protein results in increased secretion of CholesterolixnTO-901317 results in increased expression of ABCA1 mRNAixnNPC1 protein affects the reaction [fingolimod results in increased expression of ABCA1 protein]ixn[fingolimod results in increased abundance of 27-hydroxycholesterol] which results in increased expression of ABCA1 mRNA11784781title0Contrasting, species-dependent modulation of copper-mediated neurotoxicity by the Alzheimer''s disease amyloid precursor protein.abstract130The amyloid precursor protein (APP) of Alzheimer''s disease (AD) has a copper binding domain (CuBD) located in the N-terminal cysteine-rich region that can strongly bind copper(II) and reduce it to Cu(I) in vitro. The CuBD sequence is similar among the APP family paralogs [amyloid precursor-like proteins (APLP1 and APLP2)] and its orthologs (including Drosophila melanogaster, Xenopus laevis, and Caenorhabditis elegans), suggesting an overall conservation in its function or activity. The APP CuBD is involved in modulating Cu homeostasis and amyloid beta peptide production. In this paper, we demonstrate for the first time that Cu-metallated full-length APP ectodomain induces neuronal cell death in vitro. APP Cu neurotoxicity can be induced directly or potentiated through Cu(I)-mediated oxidation of low-density lipoprotein, a finding that may have important implications for the role of lipoproteins and membrane cholesterol composition in AD. Cu toxicity induced by human APP, Xenopus APP, and APLP2 CuBDs is dependent on conservation of histidine residues at positions corresponding to 147 and 151 of human APP. Intriguingly, APP orthologs with different amino acid residues at these positions had dramatically altered Cu phenotypes. The corresponding C. elegans APL-1 CuBD, which has tyrosine and lysine residues at positions 147 and 151, respectively, strongly protected against Cu-mediated lipid peroxidation and neurotoxicity in vitro. Replacement of histidines 147 and 151 with tyrosine and lysine residues conferred this neuroprotective Cu phenotype to human APP, APLP2, and Xenopus APP CuBD peptides. Moreover, we show that the toxic and protective CuBD phenotypes are associated with differences in Cu binding and reduction. These studies identify a significant evolutionary change in the function of the CuBD in modulating Cu metabolism. Our findings also suggest that targeting of inhibitors to histidine residues at positions 147 and 151 of APP could significantly alter the oxidative potential of APP.chemCOPPERdiseaseNERVE DEGENERATIONgeneAPL-1geneAPPgeneAPLP2action termbindingaction termreductionaction termresponse to substanceixnAPL-1 has a real or putative therapeutic role towards Nerve DegenerationixnAPP protein binds to and results in increased reduction of CopperixnAPP plays a role in or acts as a marker for Nerve DegenerationixnCopper plays a role in or acts as a marker for Nerve DegenerationixnAPL-1 protein binds to and results in decreased susceptibility to CopperixnAPLP2 plays a role in or acts as a marker for Nerve DegenerationixnAPLP2 protein binds to and results in increased susceptibility to CopperixnAPP protein results in increased susceptibility to CopperixnAPP protein binds to and results in increased susceptibility to CopperixnAPP protein binds to and results in increased susceptibility to Copper17684035title0Transcript of protein kinase A knock-down modulates feeding behavior and neuropeptide Y gene expression in phenylpropanolamine-treated rats.abstract141Neuropeptide Y (NPY) is an appetite-controlling neuromodulator that contributes to the appetite-suppressing effect of phenylpropanolamine (PPA). Aims of this study were to investigate whether protein kinase A (PKA) signaling is involved in regulating NPY gene expression and PPA-induced anorexia. Rats were given daily with PPA for 5 days. Changes in daily food intake and hypothalamic NPY, PKA, cAMP response element binding protein (CREB), and pro-opiomelanocortin (POMC) gene expression were measured and compared. To further determine if PKA was involved, intracerebroventricular infusions of antisense oligodeoxynucleotide were performed at 60 min before daily PPA treatment in freely moving rats. Results showed that daily PKA, CREB, and POMC expression were increased following PPA treatment, which showed a closely reverse relationship with alterations of decreased feeding behaviors and NPY mRNA levels. Results also showed that PKA knock-down could block PPA-induced anorexia as well as restore NPY mRNA level, indicating the involvement of PKA signaling in the regulation of NPY gene expression. It is suggested that hypothalamic PKA signaling may participate in the central regulation of PPA-mediated appetite suppression via the modulation of hypothalamic NPY gene expression. The present findings reveal that manipulations at the molecular level of PKA or cAMP may allow the development of therapeutic agents to improve the undesirable properties of PPA or other amphetamine-like anorectic drugs.chemPHENYLPROPANOLAMINEdiseaseANOREXIAgenePOMCgenePRKAR2AgeneNPYgeneCREB1action termexpressionaction termactivityixnPhenylpropanolamine plays a role in or acts as a marker for AnorexiaixnPhenylpropanolamine results in decreased expression of NPY mRNAixnPhenylpropanolamine results in increased expression of PRKAR2A mRNAixnPhenylpropanolamine results in increased expression of CREB1 mRNAixnPhenylpropanolamine results in increased expression of POMC mRNAixnPhenylpropanolamine results in increased expression of and results in increased activity of CREB1 proteinixnPhenylpropanolamine results in decreased expression of NPY proteinixnPhenylpropanolamine results in increased expression of PRKAR2A proteinixnPhenylpropanolamine results in increased expression of POMC protein11940550title0Cardiovascular influences of alpha1b-adrenergic receptor defect in mice.abstract73BACKGROUND: The alpha1-adrenergic receptors (alpha1-ARs) play a key role in cardiovascular homeostasis. However, the functional role of alpha1-AR subtypes in vivo is still unclear. The aim of this study was to evaluate the cardiovascular influences of alpha1b-AR.
METHODS AND RESULTS: In transgenic mice lacking alpha1-AR (KO) and their wild-type controls (WT), we evaluated blood pressure profile and cardiovascular remodeling induced by the chronic administration (18 days via osmotic pumps) of norepinephrine, angiotensin II, and subpressor doses of phenylephrine. Our results indicate that norepinephrine induced an increase in blood pressure levels only in WT mice. In contrast, the hypertensive state induced by angiotensin II was comparable between WT and KO mice. Phenylephrine did not modify blood pressure levels in either WT or KO mice. The cardiac hypertrophy and eutrophic vascular remodeling evoked by norepinephrine was observed only in WT mice, and this effect was independent of the hypertensive state because it was similar to that observed during subpressor phenylephrine infusion. Finally, the cardiac hypertrophy induced by thoracic aortic constriction was comparable between WT and KO mice.
CONCLUSIONS: Our data demonstrate that the lack of alpha1b-AR protects from the chronic increase of arterial blood pressure induced by norepinephrine and concomitantly prevents cardiovascular remodeling evoked by adrenergic activation independently of blood pressure levels.chemPHENYLEPHRINEchemNOREPINEPHRINEdiseaseCARDIOMEGALYgeneAGTgeneADRA1BixnADRA1B plays a role in or acts as a marker for CardiomegalyixnNorepinephrine plays a role in or acts as a marker for CardiomegalyixnPhenylephrine plays a role in or acts as a marker for Cardiomegaly3039113title0On the relationship between clonidine hypotension and brain beta-endorphin in the spontaneously hypertensive rat: studies with alpha adrenergic and opiate blockers.abstract165The relationship between the centrally mediated hypotensive and bradycardic effects of clonidine to central alpha-2 adrenergic receptor activation, brain beta-endorphin (BE) release and opiate receptor activation was studied in chloralose-anesthetized spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats, using a cerebroventricular perfusion system. Prior treatment of SHRs with i.v. naloxone (2 or 4 mg/kg) or i.c.v. yohimbine (10 or 20 micrograms/kg) reduced the hypotension and bradycardia induced by i.c.v. clonidine, but in Wistar-Kyoto rats naloxone had no similar blocking effects. Prazosin (20 micrograms/kg i.c.v.) reduced the clonidine bradycardia but not the hypotension in SHRs. Hypotension in the SHRs due to i.c.v. alpha-methylnorepinephrine (20 micrograms/kg) was reduced by both naloxone and yohimbine whereas alpha-methylnorepinephrine bradycardia was reduced by yohimbine but not by naloxone. Prior hypothalamic lesions in the SHRs reduced clonidine hypotension, but not bradycardia, and interfered with naloxone blockade of the residual clonidine hypotensive effect. Clonidine lowered immunoreactive BE levels in SHR hypothalamus, medulla and pituitary but did not change BE levels in the i.c.v. perfusate. The findings support the idea that in the SHRs, clonidine hypotension results from alpha-2 adrenergic stimulation of brain, causing BE release and central opiate receptor activation, and they suggest that the hypothalamus is involved in these interactions. Also, clonidine hypotension and bradycardia appear to involve different mechanisms in brain.chemNALOXONEchemPRAZOSINchemNORDEFRINchemYOHIMBINEchemCLONIDINEdiseaseBRADYCARDIAdiseaseHYPOTENSIONgenePOMCaction termexpressionixnClonidine plays a role in or acts as a marker for BradycardiaixnClonidine plays a role in or acts as a marker for HypotensionixnNaloxone has a real or putative therapeutic role towards BradycardiaixnNordefrin plays a role in or acts as a marker for HypotensionixnPrazosin has a real or putative therapeutic role towards BradycardiaixnYohimbine has a real or putative therapeutic role towards HypotensionixnNaloxone has a real or putative therapeutic role towards HypotensionixnNordefrin plays a role in or acts as a marker for BradycardiaixnYohimbine has a real or putative therapeutic role towards BradycardiaixnClonidine results in decreased expression of POMC protein18990726title0Lung development in the Holtzman rat is adversely affected by gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.abstract1232,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that elicits a wide range of toxic effects on the developing organism. In this study, we demonstrate that the fetal and neonatal rat lung contains a responsive Ahr-signaling pathway which upon activation by a gestational exposure to TCDD, leads to altered lung development. Pregnant Holtzman rats received a single oral dose of TCDD (1.5 or 6 microg/kg) on gestation day (GD) 10 or a vehicle control with fetal and neonatal analysis occurring on GD20 or postnatal day (PND) 7. Components of the aryl hydrocarbon receptor (Ahr) signaling pathway (Ahr and Arnt) were identified in the fetal and neonatal lung tissue through the use of real-time PCR and immunohistochemical staining at both time points. Additionally, the Ahr-signaling pathway was found to be responsive to the gestational TCDD exposure as demonstrated by the induction of Cyp1a1, Cyp1b1, and Ahrr in both fetal and neonatal lung tissue. Morphometric analysis of GD20 and PND7 fixed lung tissue sections revealed that treated pups had significant decreases in total airspace area while having significantly wider tissue septa separating the airspaces as well as a decreased dry lung weight to body weight ratio when compared with controls; indicative of lung immaturity and hypoplasia. Finally, the assessment of respiratory mechanics on PND7 pups revealed functionally different pressure-volume curves in TCDD-exposed pups when compared with control animals. Together, these data identify a responsive Ahr-signaling pathway in the developing lung which may be related to the pulmonary immaturity and hypoplasia induced by TCDD and demonstrates that gestational exposure to TCDD alters lung development in such a manner that changes in lung morphology are associated with functional differences in respiratory mechanics.chemTETRACHLORODIBENZODIOXINdiseaseRESPIRATORY SYSTEM ABNORMALITIESgeneCYP1B1geneSFTPBgeneCYP1A1geneSFTPA1geneSFTPDgeneAQP5genePDPNgeneAHRRaction termexpressionixnTetrachlorodibenzodioxin plays a role in or acts as a marker for Respiratory System AbnormalitiesixnTetrachlorodibenzodioxin results in increased expression of CYP1A1 mRNAixnTetrachlorodibenzodioxin results in increased expression of CYP1B1 mRNAixnTetrachlorodibenzodioxin results in increased expression of AHRR mRNAixnTetrachlorodibenzodioxin results in increased expression of SFTPA1 mRNAixnTetrachlorodibenzodioxin results in increased expression of SFTPB mRNAixnTetrachlorodibenzodioxin results in decreased expression of AQP5 mRNAixnTetrachlorodibenzodioxin results in decreased expression of SFTPD mRNAixnTetrachlorodibenzodioxin results in decreased expression of PDPN mRNA17292621title0In vitro and in vivo profiling of CHF5022 and CHF5074 Two beta-amyloid1-42 lowering agents.abstract92Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may delay or prevent the onset of Alzheimer''s disease (AD). A subset of NSAIDs, including flurbiprofen, has been shown to selectively inhibit the production of beta-amyloid(1-42) (Abeta42), independently from their cyclooxygenase (COX) inhibiting activity. We evaluated the in vitro and in vivo profiles of CHF5022 and CHF5074, two flurbiprofen analogues. The in vitro Abeta inhibiting activity was evaluated in a human neuroglioma cell line (H4) carrying the double Swedish mutation (K595N/M596L) of the human amyloid precursor protein (APPsw). The in vitro anti-COX activity was evaluated using human recombinant enzymes isolated from transfected Sf-9 cells. The in vivo pharmacokinetic and pharmacodynamic profiles of the two compounds were evaluated in young APPsw transgenic mice (Tg2576) after oral gavage (100 or 300mgkg(-1) day(-1) for 4-5 days) and after medicated diet (375ppm for 4 weeks). R-Flurbiprofen was used as comparator. In vitro, CHF5022 and CHF5074 were found to be 3- and 7-fold more potent than R-flurbiprofen in inhibiting Abeta42 secretion (IC(50)s of 92, 40 and 268microM, respectively). Differently from R-flurbiprofen, CHF5022 and CHF5074 did not affect COX-1 (at 100microM) and COX-2 (at 300microM) activity. Similarly to R-flurbiprofen, no significant alteration in the expression profile of a subset of Notch intracellular domain-responsive genes was observed with either CHF5022 or CHF5074. In Tg2576 mice, CHF5022 was well tolerated when administered by oral gavage (100mgkg(-1) day(-1) for 5 days) or by medicated diet (56mg kg(-1) day(-1) for 4 weeks). R-Flurbiprofen was poorly tolerated in the diet (32mgkg(-1) day(-1)) with 55% of the animals dying during the first week of treatment. After 4-5 days of oral gavage, CHF5022 and CHF5074 plasma and brain levels at 3h were found to increase with the dose, leading to brain concentrations of about 10% and 5% of the corresponding plasma concentrations, respectively. In animals fed for 4 weeks with compound-supplemented diet, mean plasma (580microM) and brain (20microM) Cyrillic) concentrations of CHF5022 were 8 and 15 times higher than those of R-flurbiprofen. Plasma Abeta42 concentration was dose-dependently decreased by CHF5022 and CHF5074. Brain Abeta levels (formic acid-extractable) were not significantly affected by either compound, although Abeta42 levels tended to inversely correlate (P=0.105) with CHF5022 concentration in the brain. CHF5022 and CHF5074 thus appear to have a promising in vitro and in vivo profile. This warrants further evaluation of their long-term effects on Abeta brain pathology.chemFLURBIPROFENchem1-(3',4'-DICHLORO-2-FLUORO(1,1'-BIPHENYL)-4-YL)CYCLOPROPANECARBOXYLIC ACIDchemCHF 5022diseaseDEATHgeneAPPgenePTGS1geneKLF10geneKTN1action termexpressionaction termsecretionaction termactivityixnFlurbiprofen results in decreased secretion of APP proteinixnCHF 5022 results in decreased expression of KTN1 mRNAixn1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid results in decreased activity of PTGS1 proteinixnCHF 5022 results in decreased secretion of APP proteinixn1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid results in decreased secretion of APP proteinixnCHF 5022 results in decreased secretion of APP proteinixnFlurbiprofen plays a role in or acts as a marker for DeathixnCHF 5022 results in decreased expression of KLF10 mRNAixn1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid results in decreased secretion of APP protein8318674title0Pulmonary edema and shock after high-dose aracytine-C for lymphoma; possible role of TNF-alpha and PAF.abstract104Four out of 23 consecutive patients treated with high-dose Ara-C for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of fever, diarrhea, shock, pulmonary edema, acute renal failure, metabolic acidosis, weight gain and leukocytosis. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during Ara-C infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome, we hypothesize that high-dose Ara-C may be associated with cytokine release.chemCYTARABINEdiseaseWEIGHT GAINdiseaseACUTE KIDNEY INJURYdiseaseFEVERdiseaseACIDOSISdiseasePULMONARY EDEMAdiseaseSHOCKdiseaseLEUKOCYTOSISdiseaseDIARRHEAgeneTNFaction termexpressionixnCytarabine plays a role in or acts as a marker for FeverixnCytarabine plays a role in or acts as a marker for AcidosisixnCytarabine plays a role in or acts as a marker for Pulmonary EdemaixnCytarabine plays a role in or acts as a marker for DiarrheaixnCytarabine plays a role in or acts as a marker for ShockixnCytarabine plays a role in or acts as a marker for Acute Kidney InjuryixnCytarabine plays a role in or acts as a marker for Weight GainixnCytarabine plays a role in or acts as a marker for LeukocytosisixnCytarabine results in increased expression of TNF protein12387356title0Glutamate/aspartate transporter (GLAST), taurine transporter and metallothionein mRNA levels are differentially altered in astrocytes exposed to manganese chloride, manganese phosphate or manganese sulfate.abstract207Manganese (Mn)-induced neurotoxicity can occur due to environmental exposure (air pollution, soil, water) and/or metabolic aberrations (decreased biliary excretion). High brain manganese levels lead to oxidative stress, as well as alterations in neurotransmitter metabolism with concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain regional Mn concentration, it is likely that in pathological conditions, Mn concentration can reach between 100 and 500 microM. Environmental Mn exposure as a result of methylcyclopentadienyl manganese tricarbonyl (MMT) combustion is in the form of phosphate or sulfate (MnPO4, MnSO4, respectively). Pharmacokinetic studies have shown that the Mn salt will determine the rate of transport into the brain: MnCl2 > MnSO4 > MnPO4. The salt-specific neurotoxicity of these species is unknown. The primary goal of this study was to examine gene expression of glutamate/aspartate transporter (GLAST), taurine transporter (tau-T), and metallothionein-I (MT-I) in astrocytes exposed to manganese chloride (MnCl2), manganese sulfate (MnSO4), and manganese phosphate (MnPO4). We hypothesized that the effects of MnPO4 and MnSO4 exposure on GLASTexpression in astrocytes would be similar to those induced by MnCl2, since irrespective of salt species exposure, once internalized by astrocytes, the Mn ion would be identically complexed. At the same time, we hypothesized that the magnitude of the effect would be salt-dependent, since the chemical speciation would determine the rate of intracellular uptake of Mn. MnCl2 caused a significant overall decrease (P < 0.0001) in astrocytic GLAST mRNA levels with MnSO4 causing a moderate decrease. MnPO4 exposure did not alter GLAST mRNA in astrocytes. We also sought to examine astrocytic metallothionein and taurine transporter gene expression as markers of manganese exposure. Our findings suggest that manganese chloride significantly decreased (P < 0.0001) astrocytic metallothionein mRNA compared to both the sulfate and phosphate species. However, astrocytic taurine transporter mRNA was not affected by Mn exposure, irrespective of the salt species. These data are consistent with the hypothesis that astrocytic neurotoxicity due to Mn exposure is dependent upon its species, with solubility, and by inference, intracellular concentration, representing a major determinant of its neurotoxicity.chemMANGANESE SULFATEchemMANGANESE CHLORIDEchemMANGANESE PHOSPHATEchemMANGANESEchemIRONdiseaseNEUROBEHAVIORAL MANIFESTATIONSdiseaseMANGANESE POISONINGgeneSLC1A3geneMT1AgeneSOD3action termexpressionaction termcotreatmentixnmanganese chloride results in decreased expression of MT1A mRNAixnManganese plays a role in or acts as a marker for Neurobehavioral Manifestationsixnmanganese chloride results in decreased expression of SLC1A3 mRNAixnmanganese phosphate plays a role in or acts as a marker for Manganese Poisoningixnmanganese sulfate plays a role in or acts as a marker for Manganese Poisoningixnmanganese sulfate results in decreased expression of SLC1A3 mRNAixnmanganese sulfate results in decreased expression of MT1A mRNAixnmanganese phosphate results in decreased expression of MT1A mRNAixn[manganese chloride co-treated with Iron] affects the expression of SOD3 mRNA19429072title0Therapeutic potential of alpha2 adrenoceptor antagonism for antipsychotic-induced extrapyramidal motor disorders.abstract114We examined the effects of JP-1302 (a selective alpha2C antagonist), BRL-44408 (a selective alpha2A antagonist) and yohimbine (a non-selective alpha2 antagonist) on haloperidol-induced bradykinesia and catalepsy in mice to elucidate the role of alpha2 adrenoceptor subtypes in modifying extrapyramidal motor disorders. JP-1302 (0.1-1 mg/kg, s.c.) dose-dependently ameliorated haloperidol-induced bradykinesia in the pole-test and reversed the catalepsy time increased by haloperidol. Antibradykinetic and anticataleptic actions of JP-1302 were statistically significant at 0.3 and 1 mg/kg, and these doses did not alter the ambulatory distance, rearing or center-perimeter residence time in the open-field test. BRL-44408 (1-10 mg/kg, s.c.) and yohimbine (0.3-3 mg/kg, i.p.) also ameliorated haloperidol-induced bradykinesia and catalepsy. However, both agents significantly decreased ambulatory distance and rearing in the open-field test, possibly reflecting their anxiogenic actions associated with alpha2A antagonism. The present study shows for the first time that blockade of alpha2C receptors can alleviate antipsychotic-induced extrapyramidal motor disorders without affecting gross behaviors.chemYOHIMBINEchemJP-1302chemBRL 44408chemHALOPERIDOLdiseaseHYPOKINESIAdiseaseCATALEPSYgeneADRA2CgeneADRA2Aaction termbindingaction termactivityixnYohimbine has a real or putative therapeutic role towards CatalepsyixnBRL 44408 has a real or putative therapeutic role towards CatalepsyixnBRL 44408 binds to and results in decreased activity of ADRA2A proteinixnYohimbine has a real or putative therapeutic role towards HypokinesiaixnBRL 44408 has a real or putative therapeutic role towards HypokinesiaixnHaloperidol plays a role in or acts as a marker for HypokinesiaixnJP-1302 has a real or putative therapeutic role towards CatalepsyixnJP-1302 binds to and results in decreased activity of ADRA2C proteinixnHaloperidol plays a role in or acts as a marker for CatalepsyixnJP-1302 has a real or putative therapeutic role towards Hypokinesia11686837title0Protective effect of rebamipide on indomethacin-induced intestinal damage in rats.abstract83BACKGROUND AND AIM: We evaluated the effect of rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid), a novel anti-ulcer drug, on indomethacin-induced small intestinal lesions in rats.
METHODS: The animals were administered indomethacin (10 mg/kg, s.c.), and they were killed 24 h later. Rebamipide (30-300 mg/kg) was administered p.o. twice, 30 min before, and 6 h after indomethacin.
RESULTS: Indomethacin caused hemorrhagic lesions in the rat small intestine, accompanied by an increase in enterobacterial translocation, inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO) activities, as well as thiobarbituric acid (TBA) reactants, and these changes were significantly prevented by the supplementation with 16,16-dimethyl prostaglandin E2 (dmPGE2; 10 microg/kg, i.v.) or the pretreatment of animals with the antibiotic ampicillin. Treatment of the animals with rebamipide dose-dependently prevented the development of intestinal lesions, and this effect was mimicked by i.v. administration of superoxide dismutase (SOD: 3000 U/kg) + catalase (CAT: 5000 U/kg). The protection by rebamipide was accompanied by a significant suppression of the increase in both MPO and iNOS activities, and a complete inhibition of the increase in TBA reactants, while SOD + CAT significantly inhibited the increase of MPO activity and TBA reactants, but not iNOS activity. The bacterial translocation following indomethacin was also significantly decreased by either rebamipide or SOD + CAT.
CONCLUSION: These results confirmed the importance of enterobacteria and iNOS/NO in the pathogenesis of indomethacin-induced small intestinal lesions, and suggested that rebamipide prevents the development of these lesions, probably by its radical scavenging action.chemINDOMETHACINchemAMPICILLINchemREBAMIPIDEchem16,16-DIMETHYLPROSTAGLANDIN E2diseaseINTESTINAL DISEASESgeneNOS2geneMPOaction termreactionaction termactivityixnIndomethacin plays a role in or acts as a marker for Intestinal Diseasesixnrebamipide has a real or putative therapeutic role towards Intestinal Diseasesixn16,16-Dimethylprostaglandin E2 inhibits the reaction [Indomethacin results in increased activity of NOS2 protein]ixn16,16-Dimethylprostaglandin E2 inhibits the reaction [Indomethacin results in increased activity of MPO protein]ixnAmpicillin inhibits the reaction [Indomethacin results in increased activity of NOS2 protein]ixnAmpicillin inhibits the reaction [Indomethacin results in increased activity of MPO protein]ixnrebamipide inhibits the reaction [Indomethacin results in increased activity of NOS2 protein]ixnrebamipide inhibits the reaction [Indomethacin results in increased activity of MPO protein]ixnIndomethacin results in increased activity of NOS2 proteinixnIndomethacin results in increased activity of MPO protein19788892title0Effect of fucoidan on aspirin-induced stomach ulceration in rats.abstract66In this study, the effects of fucoidan on aspirin-induced ulcers in rats were evaluated: both biochemical and immunological parameters were taken into consideration. The status of stomach tissue glycogen storage and histological changes were also examined. Examination of basic biochemical parameters showed significant (p<0.01) alterations in aspartate (AST) and alanine (ALT) transaminases in ulcer-induced rats. Also, moderate alterations (p<0.05) were observed in the levels of cholesterol and blood urea nitrogen (BUN). Histopathological examination showed neutrophil infiltration and inflammation in oxyntic cells with altered glycogen storage. Analysis of serum cytokines of aspirin-induced rats showed a moderate decrease in interleukin-10 (IL-10) with considerable increase of interleukin-6 (IL-6) and interferon-gamma (INF-gamma) when compared with control. Administration of fucoidan showed considerable (p<0.05) protection against ulceration by inhibiting the acute alterations of AST, ALT, cytokines and stomach glycogen. However, aggravated serum INF-gamma was observed in the fucoidan-pretreated group. These findings suggest that the anti-ulcer property of fucoidan might contribute in protecting the inflammatory cytokine-mediated oxidative damage to gastric mucosa.chemFUCOIDANchemASPIRINdiseaseSTOMACH ULCERgeneGPTgeneIL6geneIL10geneIFNGaction termexpressionaction termreactionixnAspirin plays a role in or acts as a marker for Stomach UlcerixnAspirin results in increased expression of GPT proteinixnAspirin results in increased expression of IL10 proteinixnAspirin results in increased expression of IFNG proteinixnfucoidan inhibits the reaction [Aspirin results in increased expression of IL6 protein]ixnfucoidan has a real or putative therapeutic role towards Stomach Ulcerixnfucoidan inhibits the reaction [Aspirin results in increased expression of GPT protein]ixnAspirin results in increased expression of IL6 proteinixnfucoidan promotes the reaction [Aspirin results in increased expression of IFNG protein]ixnfucoidan promotes the reaction [Aspirin results in increased expression of IL10 protein]20452335title0Potential chemoprevention of diethylnitrosamine-initiated and 2-acetylaminofluorene-promoted hepatocarcinogenesis by zerumbone from the rhizomes of the subtropical ginger (Zingiber zerumbet).abstract192Zerumbone (ZER), a monosesquiterpene found in the subtropical ginger (Zingiber zerumbet Smith), possesses antiproliferative properties to several cancer cells lines, including the cervical, skin and colon cancers. In this study, the antitumourigenic effects of ZER were assessed in rats induced to develop liver cancer with a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg) and dietary 2-acetylaminofluorene (AAF) (0.02%). The rats also received intraperitoneal ZER injections at 15, 30 or 60 mg/kg body wt. twice a week for 11 weeks, beginning week four post-DEN injection. The hepatocytes of positive control (DEN/AAF) rats were smaller with larger hyperchromatic nuclei than normal, showing cytoplasmic granulation and intracytoplasmic violaceous material, which were characteristics of hepatocarcinogenesis. Histopathological evaluations showed that ZER protects the rat liver from the carcinogenic effects of DEN and AAF. Serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (AP) and alpha-fetoprotein (AFP) were significantly lower (P<0.05) in ZER-treated than untreated rats with liver cancer. The liver malondialdehyde (MDA) concentrations significantly (P<0.05) increased in the untreated DEN/AAF rats indicating hepatic lipid peroxidation. There was also significant (P<0.05) reduction in the hepatic tissue glutathione (GSH) concentrations. The liver sections of untreated DEN/AAF rats also showed abundant proliferating cell nuclear antigen (PCNA), while in ZER-treated rats the expression of this antigen was significantly (P<0.05) lowered. By the TUNEL assay, there were significantly (P<0.05) higher numbers of apoptotic cells in DEN/AAF rats treated with ZER than those untreated. Zerumbone treatment had also increased Bax and decreased Bcl-2 protein expression in the livers of DEN/AAF rats, which suggested increased apoptosis. Even after 11 weeks of ZER treatment, there was no evidence of abnormality in the liver of normal rats. This study suggests that ZER reduces oxidative stress, inhibits proliferation, induces mitochondria-regulated apoptosis, thus minimising DEN/AAF-induced carcinogenesis in rat liver. Therefore, ZER has great potential in the treatment of liver cancers.chemZERUMBONEchemDIETHYLNITROSAMINEchem2-AMINOFLUORENEdiseaseLIVER NEOPLASMSgeneBCL2genePCNAgeneBAXaction termreactionaction termexpressionaction termcotreatmentixnDiethylnitrosamine plays a role in or acts as a marker for Liver Neoplasmsixn2-aminofluorene plays a role in or acts as a marker for Liver Neoplasmsixnzerumbone has a real or putative therapeutic role towards Liver Neoplasmsixnzerumbone promotes the reaction [[2-aminofluorene co-treated with Diethylnitrosamine] results in increased expression of BAX protein]ixn[2-aminofluorene co-treated with Diethylnitrosamine] results in increased expression of PCNA proteinixnzerumbone inhibits the reaction [[2-aminofluorene co-treated with Diethylnitrosamine] results in increased expression of PCNA protein]ixnzerumbone inhibits the reaction [[2-aminofluorene co-treated with Diethylnitrosamine] results in increased expression of BCL2 protein]ixn[2-aminofluorene co-treated with Diethylnitrosamine] results in increased expression of BAX proteinixn[2-aminofluorene co-treated with Diethylnitrosamine] results in increased expression of BCL2 protein22095879title0Off-target immune cell toxicity caused by AG-012986, a pan-CDK inhibitor, is associated with inhibition of p38 MAPK phosphorylation.abstract133AG-012986 is a pan-CDK (cyclin-dependent kinase) inhibitor that has in vitro and in vivo antitumor properties but was stopped in development due in part to rapid bone-marrow-independent white blood cell toxicity in preclinical studies and the potential for acute and delayed immunosuppression in humans. Because peripheral lymphocytes are largely nonproliferating, it was hypothesized the toxicity of AG-012986 was due to an off-target mechanism and not driven by the intended pharmacology. We show the toxicity mechanism in primary human immune cells is caspase driven. T-cells treated with AG-012986 and acutely stimulated through the T-cell receptor exhibited decreased toxicity while still maintaining cell division inhibition. This indicated that the pharmacology of AG-012986 functioned as expected but the toxicity had now been decoupled through activation. Induced phosphorylation of p38 and IL-2 production was impaired with AG-012986. Thus, AG-012986 could cause apoptosis of T-cells by targeting upstream kinases in the p38 Mitogen-activated protein kinase (MAPK) pathway and impairing cellular survival.chemAG-012986diseaseNECROSISgeneCASP7geneCDK2geneCDK4geneCASP3genePARP1geneCDK9geneCDK5geneCDK1action termcleavageaction termactivityixnAG-012986 results in decreased activity of CDK2 proteinixnAG-012986 results in decreased activity of CDK4 proteinixnAG-012986 results in decreased activity of CDK5 proteinixnAG-012986 results in decreased activity of CDK9 proteinixnAG-012986 results in decreased activity of CDK1 proteinixnAG-012986 results in increased activity of CASP3 proteinixnAG-012986 results in increased activity of CASP7 proteinixnAG-012986 plays a role in or acts as a marker for NecrosisixnAG-012986 results in increased cleavage of PARP1 protein20305041title0Novel protective mechanisms of antidepressants against 3-nitropropionic acid induced Huntington''s-like symptoms: a comparative study.abstract135Huntington''s disease (HD) is characterized by progressive degeneration of neurons in the striatum, cortex and other parts of the brain, causing motor and cognitive dysfunction. 3-Nitropropionic acid (3-NP) is a well-known mycotoxin that significantly induces motor dysfunction in animals. Studies suggested the involvement of oxidative stress and nitric oxide mechanisms in HD pathogenesis. Clinical reports have also indicated the neuroprotective potential of antidepressants. Therefore, the present study has been designed to elucidate and compare the mechanistic role of different antidepressants (sertraline, venlafaxine, imipramine and trazodone) and their interaction with nitric oxide modulators if any, against 3-NP-induced neurotoxicity. Systemic 3-NP (10 mg/kg) administration for 14 days significantly reduced locomotor activity, body weight, motor coordination, oxidative defense and impaired mitochondrial complex enzyme activities in the striatum. Sertraline, venlafaxine, imipramine and trazodone treatments significantly improved behavioral, oxidative defense and mitochondrial complex enzyme activities as compared with the 3-NP-treated group. Systemic L-arginine (50 mg/kg) pretreatment with sub-effective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) and trazodone (10 mg/kg) for 14 days significantly attenuated their protective effect. Similarly, L-nitro-arginine methyl ester (L-NAME) (10 mg/kg) pretreatment with sub-effective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) and trazodone (10 mg/kg) for 14 days significantly potentiated their protective effects which were significant as compared with their effect alone, respectively. The results of the present study suggest that a nitric oxide mechanism might be involved in their protective effect against 3-NP-induced neurotoxicity.chemTRAZODONEchemIMIPRAMINEchemNITRIC OXIDEchemSERTRALINEchem3-NITROPROPIONIC ACIDchemVENLAFAXINEdiseaseDEPRESSIVE DISORDERdiseaseHUNTINGTON DISEASEgeneCATaction termreactionaction termactivityixn3-nitropropionic acid plays a role in or acts as a marker for Huntington DiseaseixnSertraline has a real or putative therapeutic role towards Depressive Disorderixnvenlafaxine has a real or putative therapeutic role towards Depressive DisorderixnImipramine has a real or putative therapeutic role towards Depressive DisorderixnTrazodone has a real or putative therapeutic role towards Depressive DisorderixnNitric Oxide promotes the reaction [Sertraline inhibits the reaction [3-nitropropionic acid results in decreased activity of CAT protein]]ixnNitric Oxide promotes the reaction [venlafaxine inhibits the reaction [3-nitropropionic acid results in decreased activity of CAT protein]]ixnvenlafaxine inhibits the reaction [3-nitropropionic acid results in decreased activity of CAT protein]ixnSertraline inhibits the reaction [3-nitropropionic acid results in decreased activity of CAT protein]ixn3-nitropropionic acid results in decreased activity of CAT protein17961222title0Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin.abstract148BACKGROUND: Acute cutaneous neurogenic inflammation initiated by activation of transient receptor potential vanilloid-1 (TRPV1) receptors following intradermal injection of capsaicin is mediated mainly by dorsal root reflexes (DRRs). Inflammatory neuropeptides are suggested to be released from primary afferent nociceptors participating in inflammation. However, no direct evidence demonstrates that the release of inflammatory substances is due to the triggering of DRRs and how activation of TRPV1 receptors initiates neurogenic inflammation via triggering DRRs.
RESULTS: Here we used pharmacological manipulations to analyze the roles of TRPV1 and neuropeptidergic receptors in the DRR-mediated neurogenic inflammation induced by intradermal injection of capsaicin. The degree of cutaneous inflammation in the hindpaw that followed capsaicin injection was assessed by measurements of local blood flow (vasodilation) and paw-thickness (edema) of the foot skin in anesthetized rats. Local injection of capsaicin, calcitonin gene-related peptide (CGRP) or substance P (SP) resulted in cutaneous vasodilation and edema. Removal of DRRs by either spinal dorsal rhizotomy or intrathecal administration of the GABAA receptor antagonist, bicuculline, reduced dramatically the capsaicin-induced vasodilation and edema. In contrast, CGRP- or SP-induced inflammation was not significantly affected after DRR removal. Dose-response analysis of the antagonistic effect of the TRPV1 receptor antagonist, capsazepine administered peripherally, shows that the capsaicin-evoked inflammation was inhibited in a dose-dependent manner, and nearly completely abolished by capsazepine at doses between 30-150 mug. In contrast, pretreatment of the periphery with different doses of CGRP8-37 (a CGRP receptor antagonist) or spantide I (a neurokinin 1 receptor antagonist) only reduced the inflammation. If both CGRP and NK1 receptors were blocked by co-administration of CGRP8-37 and spantide I, a stronger reduction in the capsaicin-initiated inflammation was produced.
CONCLUSION: Our data suggest that 1) the generation of DRRs is critical for driving the release of neuropeptides antidromically from primary afferent nociceptors; 2) activation of TRPV1 receptors in primary afferent nociceptors following intradermal capsaicin injection initiates this process; 3) the released CGRP and SP participate in neurogenic inflammation.chemCAPSAICINchemCAPSAZEPINEchemSPANTIDEchemBICUCULLINEdiseaseNEUROGENIC INFLAMMATIONdiseaseEDEMAgeneTAC1geneCALCAgeneTRPV1geneTACR1action termbindingaction termactivityixnCapsaicin plays a role in or acts as a marker for Neurogenic InflammationixnCALCA plays a role in or acts as a marker for Neurogenic InflammationixnTAC1 plays a role in or acts as a marker for Neurogenic InflammationixnBicuculline has a real or putative therapeutic role towards Neurogenic Inflammationixnspantide has a real or putative therapeutic role towards Neurogenic Inflammationixncapsazepine has a real or putative therapeutic role towards Neurogenic Inflammationixncapsazepine binds to and results in decreased activity of TRPV1 proteinixnspantide binds to and results in decreased activity of TACR1 proteinixnBicuculline has a real or putative therapeutic role towards Edema18291361title0Resveratrol attenuates thromboxane A2 receptor agonist-induced platelet activation by reducing phospholipase C activity.abstract121Resveratrol (3,5,4''-trihydroxystilbene) is a naturally occurring compound shown to decrease the incidence of thromboembolic disease. Although considerable data are available as to the inhibitory effect of resveratrol on the platelet aggregation and thrombopoiesis in human, its underlying mechanism, at the cellular level, has not been rigorously studied. In this experiment, we studied the effect of resveratrol and 1-[6-[[17-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione, a phospholipase C inhibitor (U-73122) on the thromboxane A2 receptor agonist (9,11-dideoxy-11 alpha,9 alpha-epoxymethanoprostaglandin F(2 alpha), U46619)-induced platelet aggregation, platelet P-selectin expression, and the activity of phospho-phospholipase C beta 3 (P-PLC beta 3) and total-phospholipase C beta 3 (T-PLC beta 3), which play key roles in the signal transduction system of platelet in human. It was found that resveratrol blocked platelet aggregation and platelet P-selectin expression induced by U46619 in a concentration-dependent manner. U-73122 and resveratrol had additive effect in inhibiting platelet aggregation and platelet P-selectin expression. Resveratrol (final concentration was 50 microM) could reduce the ratio of P-PLC beta 3 to T-PLC beta 3. Taken together, these results show that resveratrol suppresses U46619-induced platelet aggregation and P-selectin expression partly through the decrease of the activity of phospholipase C beta of platelets.chem15-HYDROXY-11 ALPHA,9 ALPHA-(EPOXYMETHANO)PROSTA-5,13-DIENOIC ACIDchem1-(6-((3-METHOXYESTRA-1,3,5(10)-TRIEN-17-YL)AMINO)HEXYL)-1H-PYRROLE-2,5-DIONEchemRESVERATROLdiseaseEMBOLISM AND THROMBOSISgenePLCB3geneTBXA2RgeneSELPaction termreactionaction termexpressionaction termbindingaction termactivityixnresveratrol has a real or putative therapeutic role towards Embolism and Thrombosisixn15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid binds to and results in increased activity of TBXA2R proteinixn15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid results in increased expression of SELP proteinixnresveratrol inhibits the reaction [15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid results in increased expression of SELP protein]ixn1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione inhibits the reaction [15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid results in increased expression of SELP protein]ixn1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione promotes the reaction [resveratrol inhibits the reaction [15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid results in increased expression of SELP protein]]ixnresveratrol promotes the reaction [1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione inhibits the reaction [15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid results in increased expression of SELP protein]]ixn15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid results in increased expression of PLCB3 protein modified formixnresveratrol inhibits the reaction [15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid results in increased expression of PLCB3 protein modified form]12296996title0Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase.abstract119Arsenic trioxide (As(2)O(3)) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) as well as in patients with APL in whom all-trans-retinoic acid and conventional chemotherapy failed. Chronic myelogenous leukemia cells are highly resistant to chemotherapeutic drugs. To determine if As(2)O(3) might be useful for the treatment of chronic myelogenous leukemia, we examined the ability of As(2)O(3) to induce apoptosis in K562 cells. In vitro cytotoxicity of As(2)O(3) was evaluated in K562 cells by a MTT assay; the IC(50) value for As(2)O(3) was determined to be 10 microM. When analyzed by agarose gel electrophoresis, the DNA fragments became evident after incubation of the cells with 20 microM As(2)O(3) for 24 h. We also found morphological changes and chromatin condensation of the cells undergoing apoptosis. Activation of caspase-3 was observed 6 h after treatment with 20 microM As(2)O(3) by a Western blot analysis. Next, we examined the MAP kinase-signaling pathway of As(2)O(3)-induced apoptosis in K562 cells. As(2)O(3) at 10 microM strongly induced the activation of p38 and JNK 1/2, while ERK 1/2 was inhibited. In addition, pretreatment of SB203580, a specific inhibitor of p38, inhibited As(2)O(3) induced apoptotic cell death. These results suggest that As(2)O(3) is able to induce the apoptotic activity in K562 cells, and its apoptotic mechanism may be associated with the activation of p38.chemARSENIC TRIOXIDEchemSB 203580diseaseLEUKEMIA, PROMYELOCYTIC, ACUTEgeneMAPK8geneMAPK3geneMAPK9geneMAPK1geneCASP3action termactivityixnarsenic trioxide results in increased activity of CASP3 proteinixnarsenic trioxide results in decreased activity of MAPK1 proteinixnarsenic trioxide results in decreased activity of MAPK3 proteinixnarsenic trioxide results in increased activity of MAPK8 proteinixnarsenic trioxide results in increased activity of MAPK9 proteinixnarsenic trioxide has a real or putative therapeutic role towards Leukemia, Promyelocytic, Acute18291360title0The radical scavenger edaravone counteracts diabetes in multiple low-dose streptozotocin-treated mice.abstract103Edaravone is a potent scavenger of hydroxyl radicals and attenuates oxidative damage-related neurodegenerative diseases. Previous studies suggest that oxidative stress plays a key role in the pathogenesis of diabetes. The present study examined the effect of edaravone on diabetes in multiple low-dose streptozotocin-treated mice. Mice treated with low-doses of streptozotocin for five consecutive days showed progressive hyperglycemia and an increased incidence of diabetes. Daily treatment with edaravone during the streptozotocin injections counteracted the multiple low-dose streptozotocin-induced hyperglycemia in a dose-dependent manner. Edaravone protected against the multiple low-dose streptozotocin-induced reduction in pancreatic insulin. The suppressive effects of edaravone were also observed when it was administered after the last injection of streptozotocin. Histochemical examination showed that multiple low-dose streptozotocin treatment caused mononuclear cell infiltration in pancreatic islets, followed by hyperglycemia, and that edaravone significantly inhibited the multiple low-dose streptozotocin-induced insulitis. Multiple low-dose streptozotocin treatment also increased the lipid peroxidation product thiobarbituric acid reactive substance in pancreatic tissues of mice, and this effect was completely inhibited by edaravone. These findings suggest that edaravone, even after streptozotocin treatment, counteracts the development of multiple low-dose streptozotocin-induced diabetes by scavenging free radicals, which are possible mediators of the immune destruction of islet beta cells.chemSTREPTOZOCINchemPHENYLMETHYLPYRAZOLONEdiseaseDIABETES MELLITUS, EXPERIMENTALdiseaseINFLAMMATIONdiseaseHYPERGLYCEMIAgeneINS1action termreactionaction termsecretionixnphenylmethylpyrazolone inhibits the reaction [Streptozocin results in decreased secretion of INS1 protein]ixnStreptozocin plays a role in or acts as a marker for Hyperglycemiaixnphenylmethylpyrazolone has a real or putative therapeutic role towards Inflammationixnphenylmethylpyrazolone has a real or putative therapeutic role towards HyperglycemiaixnStreptozocin plays a role in or acts as a marker for Diabetes Mellitus, ExperimentalixnStreptozocin results in decreased secretion of INS1 proteinixnStreptozocin plays a role in or acts as a marker for Inflammation21245496title0Natural killer cells mediate severe liver injury in a murine model of halothane hepatitis.abstract91Severe halothane (HAL)-induced hepatotoxicity occurs in one in 6000-30,000 patients by an unknown mechanism. Female sex is a risk factor in humans and rodents. We tested the hypothesis that a sex difference in natural killer (NK) cell activity contributes to HAL-induced liver injury. HAL (15 mmol/kg, ip) treatment resulted in severe liver injury by 12 h in female, wild-type BALB/cJ mice, and the magnitude of liver injury varied with stage of the estrous cycle. Ovariectomized (OVX) mice developed only mild liver injury. Plasma interferon-gamma (IFN- ) was elevated 10-fold in HAL-treated females compared with similarly treated male mice or with OVX female mice. IFN- knockout mice were resistant to severe HAL-induced liver injury. The deactivation of NK cells with anti-asialo GM1 treatment attenuated liver injury and the increase in plasma IFN- compared with immunoglobulin G-treated control mice. Mice with a mutated form of perforin, a protein involved in granule-mediated cytotoxicity, were protected from severe liver injury. Furthermore, HAL increased the activity of NK cells in vivo, as indicated by increased surface expression of CD69, an early activation marker. In response to HAL, NK cell receptor ligands on the surface of hepatocytes were expressed in a manner that can activate NK cells. These results confirm the sexual dimorphic hepatotoxic response to HAL in mice and suggest that IFN- and NK cells have essential roles in the development of severe HAL-induced hepatotoxicity.chemHALOTHANEdiseaseDRUG-INDUCED LIVER INJURYgeneCD69geneIFNGgenePRF1geneHMGB1geneTLR4action termreactionaction termexpressionaction termresponse to substanceixnHalothane results in increased expression of IFNG proteinixnIFNG plays a role in or acts as a marker for Drug-Induced Liver InjuryixnHalothane results in increased expression of HMGB1 proteinixnHalothane plays a role in or acts as a marker for Drug-Induced Liver InjuryixnIFNG protein results in increased susceptibility to HalothaneixnPRF1 protein affects the susceptibility to HalothaneixnHalothane results in increased expression of CD69 proteinixnPRF1 protein affects the reaction [Halothane results in increased expression of IFNG protein]ixnTLR4 protein affects the reaction [Halothane results in increased expression of IFNG protein]20177954title0Vogt-Koyanagi-Harada disease occurring during interferon-alpha and ribavirin therapy for chronic hepatitis C virus infection.abstract126We report a case of Vogt-Koyanagi-Harada (VKH) disease in a 30-year-old patient who was receiving interferon-alpha and ribavirin therapy for chronic hepatitis C virus infection. The intraocular inflammation responded to systemic corticosteroid and mycophenolate mofetil treatment. Physicians should be aware of the association between interferon-alpha and ribavirin therapy for hepatitis C virus infection and the development of VKH disease.chemATROPINEchemMETHYLPREDNISOLONEchemPREDNISONEchemMYCOPHENOLATE MOFETILchemPREDNISOLONE ACETATEchemRIBAVIRINdiseaseRETINAL DETACHMENTdiseaseUVEOMENINGOENCEPHALITIC SYNDROMEgeneIFNA2ixnRibavirin plays a role in or acts as a marker for Uveomeningoencephalitic SyndromeixnIFNA2 plays a role in or acts as a marker for Retinal Detachmentixnprednisolone acetate has a real or putative therapeutic role towards Uveomeningoencephalitic SyndromeixnMethylprednisolone has a real or putative therapeutic role towards Uveomeningoencephalitic SyndromeixnIFNA2 plays a role in or acts as a marker for Uveomeningoencephalitic SyndromeixnRibavirin plays a role in or acts as a marker for Retinal Detachmentixnmycophenolate mofetil has a real or putative therapeutic role towards Uveomeningoencephalitic SyndromeixnPrednisone has a real or putative therapeutic role towards Uveomeningoencephalitic SyndromeixnAtropine has a real or putative therapeutic role towards Uveomeningoencephalitic Syndrome19637760title0[The role of smoking in changing essential parameters in body homeostasis].abstract76Smoking, one of the avoidable causes of mortality, is considered a major risk factor for cardiovascular diseases, chronic obstructive pulmonary diseases, and bronchopulmonary cancer. Many studies suggest that nicotine induces vasoconstriction, not only in coronary arteries but also in peripheral vessels, hypertension, pro-atherogenic effects, due to increase of platelet activation and fatty acids concentration, alterations of endothelial-cell shapes, as well as endothelial-cell proliferation. The main affected vascular biochemical parameters are: endothelin-1, cholesterol, triglycerides, lipoproteins, C-reactive protein, nitric oxide, fibrinogen, and uric acid. Cigarette smoke induces inflammation in respiratory epithelium, through local irritation due to release of oxidants, aldehydes, acids, ammonium; impaired ciliar function, and retention of mucus and toxins, followed by infection; carcinogenesis due to oncogene-expression induced by oxidants, aromatic hydrocarbons, and nitrosamines. These effects are induced by alterations of endothelin-1, nitric oxide, IL1, IL6, TNF, and the CYP Enzyme System. Saliva is the first biological fluid encountered by the cigarette smoke. In vitro and in vivo salivary exposure to cigarette smoke has been shown to determine changes of concentrations of lactate dehydrogenase, amylase, and uric acid, in saliva--important factors of the antioxidant salivary system. Such changes may promote occurrence of upper digestive cancers.chemNICOTINEchemTOBACCO SMOKE POLLUTIONdiseaseHYPERTENSIONdiseaseLUNG NEOPLASMSdiseaseCARDIOVASCULAR DISEASESdiseasePULMONARY DISEASE, CHRONIC OBSTRUCTIVEgeneEDN1geneIL6geneTNFgeneCRPaction termexpressionixnTobacco Smoke Pollution affects the expression of EDN1ixnTobacco Smoke Pollution affects the expression of IL6ixnTobacco Smoke Pollution affects the expression of TNFixnTobacco Smoke Pollution plays a role in or acts as a marker for Pulmonary Disease, Chronic ObstructiveixnTobacco Smoke Pollution plays a role in or acts as a marker for Lung NeoplasmsixnTobacco Smoke Pollution plays a role in or acts as a marker for Cardiovascular DiseasesixnNicotine plays a role in or acts as a marker for HypertensionixnNicotine affects the expression of EDN1ixnNicotine affects the expression of CRP17047031title0Inflammation-like glial response in lead-exposed immature rat brain.abstract69Numerous studies on lead (Pb) neurotoxicity have indicated this metal to be a dangerous toxin, particularly during developmental stages of higher organisms. Astrocytes are responsible for sequestration of this metal in brain tissue. Activation of astroglia may often lead to loss of the buffering function and contribute to pathological processes. This phenomenon is accompanied by death of neuronal cells and may be connected with inflammatory events arising from the production of a wide range of cytokines and chemokines. The effects of prolonged exposure to Pb upon glial activation are examined in immature rats to investigate this potential proinflammatory effect. When analyzed at the protein level, glial activation is observed after Pb exposure, as reflected by the increased level of glial fibrillary acidic protein and S-100beta proteins in all parts of the brain examined. These changes are associated with elevation of proinflammatory cytokines. Production of interleukin (IL)-1beta and tumor necrosis factor-alpha is observed in hippocampus, and production of IL-6 is seen in forebrain. The expression of fractalkine is observed in both hippocampus and forebrain but inconsiderably in the cerebellum. In parallel with cytokine expression, signs of synaptic damage in hippocampus are seen after Pb exposure, as indicated by decreased levels of the axonal markers synapsin I and synaptophysin. Obtained results indicate chronic glial activation with coexisting inflammatory and neurodegenerative features as a new mechanism of Pb neurotoxicity in immature rat brain.chemLEAD ACETATEdiseaseLEAD POISONING, NERVOUS SYSTEMgeneSYPgeneIL6geneS100BgeneGFAPgeneIL1BgeneCX3CL1geneSYN1geneTNFaction termexpressionaction termsecretionixnlead acetate results in decreased expression of SYN1 proteinixnlead acetate results in increased secretion of TNF proteinixnlead acetate results in decreased expression of SYP proteinixnlead acetate results in increased expression of GFAP proteinixnlead acetate plays a role in or acts as a marker for Lead Poisoning, Nervous Systemixnlead acetate results in increased expression of S100B proteinixnlead acetate results in increased secretion of IL6 proteinixnlead acetate results in increased secretion of IL1B proteinixnlead acetate results in increased secretion of CX3CL1 protein12711302title0Induction of cytochrome P450 1A is required for circulation failure and edema by 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish.abstract131The mechanism of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is thought to result from changes in gene expression via the aryl hydrocarbon receptor (AHR). The induction of cytochrome P450 1A (CYP1A) in various organs is a cardinal effect of TCDD. However, whether CYP1A is involved in endpoints of TCDD toxicity is controversial. We investigated the role of CYP1A in TCDD-induced developmental toxicities using gene knock-down with morpholino antisense oligos. Exposure of zebrafish embryos to TCDD, at concentrations eliciting the hallmark endpoints of developmental toxicity, induced CYP1A in the heart and vascular endothelium throughout the body. This induction by TCDD was markedly inhibited by morpholinos to zebrafish arylhydrocarbon receptor 2 (zfAHR2-MO) and to zebrafish CYP1A (zfCYP1A-MO). The zfAHR2-MO but not the zfCYP1A-MO inhibited zfCYP1A mRNA expression, indicating the specificities of these morpholinos. Injection of either zfAHR2-MO or zfCYP1A-MO blocked the representative signs of TCDD developmental toxicity in zebrafish, pericardial edema and trunk circulation failure. The morpholinos appeared do not affect normal development in TCDD-untreated embryos. These results suggest a mediatory role of zfCYP1A induction through zfAHR2 activation in causing circulation failure by TCDD in zebrafish. This is the first molecular evidence demonstrating an essential requirement for CYP1A induction in TCDD-evoked developmental toxicities in any vertebrate species.chemTETRACHLORODIBENZODIOXINdiseaseEDEMAgeneAHR2geneCYP1Aaction termexpressionaction termactivityaction termresponse to substanceixnTetrachlorodibenzodioxin plays a role in or acts as a marker for EdemaixnAHR2 plays a role in or acts as a marker for EdemaixnCYP1A plays a role in or acts as a marker for EdemaixnAHR2 protein results in increased susceptibility to TetrachlorodibenzodioxinixnCYP1A protein results in increased susceptibility to TetrachlorodibenzodioxinixnTetrachlorodibenzodioxin results in increased expression of CYP1A proteinixnTetrachlorodibenzodioxin results in increased activity of AHR2 proteinixn[Tetrachlorodibenzodioxin results in increased activity of AHR2 protein] which results in increased expression of CYP1A mRNAixnTetrachlorodibenzodioxin results in increased expression of CYP1A mRNA18316031title0RBP4 disrupts vitamin A uptake homeostasis in a STRA6-deficient animal model for Matthew-Wood syndrome.abstract104The cellular uptake of vitamin A from its RBP4-bound circulating form (holo-RBP4) is a homeostatic process that evidently depends on the multidomain membrane protein STRA6. In humans, mutations in STRA6 are associated with Matthew-Wood syndrome, manifested by multisystem developmental malformations. Here we addressed the metabolic basis of this inherited disease. STRA6-dependent transfer of retinol from RBP4 into cultured NIH 3T3 fibroblasts was enhanced by lecithin:retinol acyltransferase (LRAT). The retinol transfer was bidirectional, strongly suggesting that STRA6 acts as a retinol channel/transporter. Loss-of-function analysis in zebrafish embryos revealed that Stra6 deficiency caused vitamin A deprivation of the developing eyes. We provide evidence that, in the absence of Stra6, holo-Rbp4 provokes nonspecific vitamin A excess in several embryonic tissues, impairing retinoic acid receptor signaling and gene regulation. These fatal consequences of Stra6 deficiency, including craniofacial and cardiac defects and microphthalmia, were largely alleviated by reducing embryonic Rbp4 levels by morpholino oligonucleotide or pharmacological treatments.chemVITAMIN AchemPHENYLTHIOUREAdiseaseMICROPHTHALMOSdiseaseMICROPHTHALMIA, SYNDROMIC 9diseaseCRANIOFACIAL ABNORMALITIESdiseaseCARDIOVASCULAR ABNORMALITIESgeneSTRA6geneRBP4geneLRATaction termexpressionaction termuptakeaction termtransportaction termbindingaction termcotreatmentaction termabundanceixn[STRA6 protein co-treated with LRAT protein] results in increased uptake of Vitamin AixnSTRA6 plays a role in or acts as a marker for Cardiovascular AbnormalitiesixnSTRA6 plays a role in or acts as a marker for Craniofacial AbnormalitiesixnSTRA6 plays a role in or acts as a marker for MICROPHTHALMIA, SYNDROMIC 9ixnSTRA6 plays a role in or acts as a marker for MicrophthalmosixnVitamin A binds to RBP4 proteinixnSTRA6 protein results in increased transport of Vitamin AixnSTRA6 protein affects the abundance of Vitamin AixnPhenylthiourea results in decreased expression of RBP4 mRNAixnPhenylthiourea results in decreased expression of RBP4 protein16210060title0Prevention of IL-1 signaling attenuates airway hyperresponsiveness and inflammation in a murine model of toluene diisocyanate-induced asthma.abstract142BACKGROUND: IL-1 is a pleotropic cytokine that has been shown to play a prominent role in asthma induced by large-molecular-weight proteins. Increased IL-1 immunostaining in the submucosa of patients with toluene diisocyanate (TDI)-induced asthma has also been observed, suggesting that this cytokine might also be important in asthma associated with low-molecular-weight chemicals.
OBJECTIVE: We sought to determine the role of IL-1 signaling in airway reactivity and inflammation by using a murine model of TDI-induced asthma.
METHODS: C57BL/6 mice were exposed to TDI by means of vapor inhalation (20 ppb; 4 hours per day, 5 days per week, for 6 weeks) and then challenged 2 weeks later by inhalation with 20 ppb TDI vapor for 1 hour.
RESULTS: Sensitized-challenged mice showed increased airway hyperresponsiveness (AHR), increased levels of TDI-specific IgG1 antibodies, airway epithelial thickening, inflammation consisting of infiltrating lymphocytes and eosinophils, and increased mRNA expression of IL-4, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in the lung. Prevention of IL-1 signaling through deletion of the IL-1 receptor type I or administration of neutralizing antibodies to both IL-1beta and IL-1alpha abrogated the development of TDI-induced asthma. A partial reduction in AHR and TDI-specific IgG1 levels was observed in mice administered anti-IL-1beta, whereas anti-IL-1alpha had no effect on either parameter. Antibodies to IL-1beta or IL-1alpha alone blocked airway inflammation and the expression of IL-4 and adhesion molecules in the lung.
CONCLUSIONS: These results suggest that IL-1 signaling is critical for AHR and airway inflammation, with IL-1beta and IL-1alpha having unique and overlapping roles in TDI-induced occupational asthma.chemTOLUENE 2,4-DIISOCYANATEdiseaseASTHMAgeneIL1AgeneVCAM1geneIL1BgeneICAM1geneIL4action termreactionaction termexpressionixnToluene 2,4-Diisocyanate plays a role in or acts as a marker for AsthmaixnToluene 2,4-Diisocyanate results in increased expression of IL4 mRNAixnToluene 2,4-Diisocyanate results in increased expression of ICAM1 mRNAixnToluene 2,4-Diisocyanate results in increased expression of VCAM1 mRNAixnIL1B protein affects the reaction [Toluene 2,4-Diisocyanate results in increased expression of IL4 mRNA]ixnIL1B protein affects the reaction [Toluene 2,4-Diisocyanate results in increased expression of ICAM1 mRNA]ixnIL1B protein affects the reaction [Toluene 2,4-Diisocyanate results in increased expression of VCAM1 mRNA]ixnIL1A protein affects the reaction [Toluene 2,4-Diisocyanate results in increased expression of IL4 mRNA]ixnIL1A protein affects the reaction [Toluene 2,4-Diisocyanate results in increased expression of ICAM1 mRNA]ixnIL1A protein affects the reaction [Toluene 2,4-Diisocyanate results in increased expression of VCAM1 mRNA]16275999title0Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells.abstract152Interactions between the novel histone deacetylase inhibitor LAQ824 and the cyclin-dependent kinase inhibitor roscovitine were examined in human leukemia cells. Pretreatment (24 hours) with a subtoxic concentration of LAQ824 (30 nmol/L) followed by a minimally toxic concentration of roscovitine (10 micromol/L; 24 hours) resulted in greater than additive effects on apoptosis in U937, Jurkat, and HL-60 human leukemia cells and blasts from three patients with acute myelogenous leukemia. These events were associated with enhanced conformational changes in Bax; mitochondrial release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor; and a marked increase in caspase activation. LAQ824/roscovitine-treated cells displayed caspase-dependent down-regulation of p21(CIP1) and Mcl-1 and a pronounced caspase-independent reduction in X-linked inhibitor of apoptosis (XIAP) expression. The lethality of this regimen was significantly attenuated by ectopic expression of XIAP, a nuclear localization signal-defective p21(CIP1) mutant, Mcl-1, and Bcl-2. Combined exposure to LAQ824 and roscovitine resulted in a significant reduction in XIAP mRNA levels and diminished phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Notably, roscovitine blocked LAQ824-mediated differentiation. Finally, LAQ824 and roscovitine individually and in combination triggered an increase in generation of reactive oxygen species; moreover, coadministration of the free radical scavenger N-acetylcysteine prevented LAQ824/roscovitine-mediated mitochondrial injury and apoptosis. Collectively, these findings suggest that combined treatment of human leukemia cells with LAQ824 and roscovitine disrupts maturation and synergistically induces apoptosis, lending further support for an antileukemic strategy combining novel histone deacetylase and cyclin-dependent kinase inhibitors.chemROSCOVITINEchemLAQ824diseaseLEUKEMIAgeneBAXgeneMCL1geneCDKN1AgeneXIAPgeneDIABLOgeneCYCSgeneAIFM1action termexpressionaction termlocalizationaction termfoldingaction termcotreatmentixnroscovitine has a real or putative therapeutic role towards LeukemiaixnLAQ824 has a real or putative therapeutic role towards Leukemiaixn[LAQ824 co-treated with roscovitine] affects the folding of BAX proteinixn[LAQ824 co-treated with roscovitine] results in decreased expression of XIAP proteinixn[LAQ824 co-treated with roscovitine] results in decreased expression of XIAP mRNAixn[LAQ824 co-treated with roscovitine] results in decreased expression of CDKN1A proteinixn[LAQ824 co-treated with roscovitine] affects the localization of CYCS proteinixn[LAQ824 co-treated with roscovitine] affects the localization of DIABLO proteinixn[LAQ824 co-treated with roscovitine] results in decreased expression of MCL1 proteinixn[LAQ824 co-treated with roscovitine] affects the localization of AIFM1 protein21424555title0Minocycline suppresses oxidative stress and attenuates fetal cardiac myocyte apoptosis triggered by in utero cocaine exposure.abstract127This study investigates the molecular mechanisms by which minocycline, a second generation tetracycline, prevents cardiac myocyte death induced by in utero cocaine exposure. Timed mated pregnant Sprague-Dawley (SD) rats received one of the following treatments twice daily from embryonic (E) day 15-21 (E15-E21): (i) intraperitoneal (IP) injections of saline (control); (ii) IP injections of cocaine (15 mg/kg BW); and (iii) IP injections of cocaine + oral administration of 25 mg/kg BW of minocycline. Pups were killed on postnatal day 15 (P15). Additional pregnant dams received twice daily IP injections of cocaine (from E15-E21) + oral administration of a relatively higher (37.5 mg/kg BW) dose of minocycline. Minocycline treatment continued from E15 until the pups were sacrificed on P15. In utero cocaine exposure resulted in an increase in oxidative stress and fetal cardiac myocyte apoptosis through activation of c-Jun-NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK)-mediated mitochondria-dependent apoptotic pathway. Continued minocycline treatment from E15 through P15 significantly prevented oxidative stress, kinase activation, perturbation of BAX/BCL-2 ratio, cytochrome c release, caspase activation, and attenuated fetal cardiac myocyte apoptosis after prenatal cocaine exposure. These results demonstrate in vivo cardioprotective effects of minocycline in preventing fetal cardiac myocyte death after prenatal cocaine exposure. Given its proven clinical safety and ability to cross the placental barrier and enter into the fetal circulation, minocycline may be an effective therapy for preventing cardiac consequences of in utero cocaine exposure.chemMINOCYCLINEchemCOCAINEdiseaseCOCAINE-RELATED DISORDERSgeneCYCSaction termreactionaction termsecretionixnMinocycline has a real or putative therapeutic role towards Cocaine-Related DisordersixnMinocycline inhibits the reaction [Cocaine results in increased secretion of CYCS protein]20164124title0Secreted protein acidic and rich in cysteine-induced cellular senescence in colorectal cancers in response to irinotecan is mediated by P53.abstract141Cellular senescence is another mechanism that can be exploited to achieve better chemosensitivity and greater tumor regression. Unlike apoptosis, cellular senescence can be induced at much lower concentrations of chemotherapy that are better tolerated by patients. We previously revealed that secreted protein acidic and rich in cysteine (SPARC), a matricellular protein, may function as a modulator of chemotherapy sensitivity by enhancing apoptosis. Here, we examine the effects of SPARC on cellular senescence in the presence of chemotherapy. Cellular senescence is induced only in sensitive colorectal cancer (CRC) cells with low concentrations of irinotecan (CPT-11). However, CPT-11-resistant cells exposed to endogenous or exogenous SPARC can also be triggered into cellular senescence. This induction is associated with higher levels of p16(INK4A) and phosphorylated p53. Knock down of p16(INK4A) reduces drug-induced senescence in all cells, but knock down and overexpression of p53 modulates senescence only in cells exposed to SPARC. Furthermore, treatment of mice with SPARC and CPT-11 leads to significantly increased cellular senescence and tumor regression. The chemosensitizing effects of SPARC in CRCs are, therefore, probably mediated in part by activating cellular senescence.chemIRINOTECANdiseaseNEOPLASMS, EXPERIMENTALgeneSPARCgeneCDKN2AgeneTP53action termexpressionaction termcotreatmentixn[irinotecan co-treated with SPARC protein] results in increased expression of CDKN2A proteinixnirinotecan has a real or putative therapeutic role towards Neoplasms, Experimentalixn[irinotecan co-treated with SPARC protein] results in increased expression of CDKN2A mRNAixnSPARC has a real or putative therapeutic role towards Neoplasms, Experimental22264228title0Activation of TRPV1 by capsaicin induces functional kinin B(1) receptor in rat spinal cord microglia.abstract102BACKGROUND: The kinin B(1) receptor (B(1)R) is upregulated by pro-inflammatory cytokines and oxydative stress, which are enhanced by transient receptor potential vanilloid subtype 1 (TRPV1) activation. To examine the link between TRPV1 and B(1)R in inflammatory pain, this study aimed to determine the ability of TRPV1 to regulate microglial B(1)R expression in the spinal cord dorsal horn, and the underlying mechanism.
METHODS: B(1)R expression (mRNA, protein and binding sites) was measured in cervical, thoracic and lumbar spinal cord in response to TRPV1 activation by systemic capsaicin (1-50 mg/kg, s.c) in rats pre-treated with TRPV1 antagonists (capsazepine or SB-366791), the antioxidant N-acetyl-L-cysteine (NAC), or vehicle. B(1)R function was assessed using a tail-flick test after intrathecal (i.t.) injection of a selective B(1)R agonist (des-Arg(9)-BK), and its microglial localization was investigated by confocal microscopy with the selective fluorescent B(1)R agonist, [N -bodipy]-des-Arg(9)-BK. The effect of i.t. capsaicin (1 g/site) was also investigated.
RESULTS: Capsaicin (10 to 50 mg/kg, s.c.) enhanced time-dependently (0-24h) B(1)R mRNA levels in the lumbar spinal cord; this effect was prevented by capsazepine (10 mg/kg, i.p.; 10 g/site, i.t.) and SB-366791 (1 mg/kg, i.p.; 30 g/site, i.t.). Increases of B(1)R mRNA were correlated with IL-1 mRNA levels, and they were significantly less in cervical and thoracic spinal cord. Intrathecal capsaicin (1 g/site) also enhanced B(1)R mRNA in lumbar spinal cord. NAC (1 g/kg/d 7 days) prevented B(1)R up-regulation, superoxide anion production and NF-kB activation induced by capsaicin (15 mg/kg). Des-Arg(9)-BK (9.6 nmol/site, i.t.) decreased by 25-30% the nociceptive threshold at 1 min post-injection in capsaicin-treated rats (10-50 mg/kg) while it was without effect in control rats. Des-Arg(9)-BK-induced thermal hyperalgesia was blocked by capsazepine, SB-366791 and by antagonists/inhibitors of B(1)R (SSR240612, 10 mg/kg, p.o.), glutamate NMDA receptor (DL-AP5, 10 g/site, i.t.), substance P NK-1 receptor (RP-67580, 10 g/site, i.t.) and nitric oxide synthase (L-NNA, 10 g/site, i.t.). The B(1)R fluorescent agonist was co-localized with an immunomarker of microglia (Iba-1) in spinal cord dorsal horn of capsaicin-treated rats.
CONCLUSION: This study highlights a new mechanism for B(1)R induction via TRPV1 activation and establishes a link between these two pro-nociceptive receptors in inflammatory pain.chemACETYLCYSTEINEchemBRADYKININ, DES-ARG(9)-chemRP 67580chemN-(3-METHOXYPHENYL)-4-CHLOROCINNAMANILIDEchemCAPSAICINchemCAPSAZEPINEchem2-((3-(1,3-BENZODIOXOL-5-YL)-3-(((6-METHOXY-2-NAPHTHYL)SULFONYL)AMINO)PROPANOYL)AMINO)-3-(4-((2,6-DIMETHYLPIPERIDINYL)METHYL)PHENYL)-N-ISOPROPYL-N-METHYLPROPANAMIDEdiseaseHYPERALGESIAgeneIL1BgeneBDKRB1action termreactionaction termexpressionixnRP 67580 has a real or putative therapeutic role towards HyperalgesiaixnCapsaicin results in increased expression of BDKRB1 mRNAixncapsazepine inhibits the reaction [Capsaicin results in increased expression of BDKRB1 mRNA]ixnN-(3-methoxyphenyl)-4-chlorocinnamanilide inhibits the reaction [Capsaicin results in increased expression of BDKRB1 mRNA]ixnCapsaicin results in increased expression of IL1B mRNAixnAcetylcysteine inhibits the reaction [Capsaicin results in increased expression of BDKRB1 mRNA]ixnbradykinin, des-Arg(9)- plays a role in or acts as a marker for Hyperalgesiaixncapsazepine has a real or putative therapeutic role towards HyperalgesiaixnN-(3-methoxyphenyl)-4-chlorocinnamanilide has a real or putative therapeutic role towards Hyperalgesiaixn2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide has a real or putative therapeutic role towards Hyperalgesia16522730title0Inactivation of Kupffer cells by gadolinium administration prevents lipopolysaccharide-induced decrease in liver insulin-like growth factor-I and IGF-binding protein-3 gene expression.abstract185Gram-negative bacterial infection or treatment of animals with bacterial lipopolysaccharide (LPS) induces a catabolic state with proteolysis, liver injury and an inhibition of the insulin-like growth factor-I (IGF-I) system. The purpose of this work was to elucidate the role of Kupffer cells in LPS-induced inhibition of the IGF-I/IGF-binding protein-3 (IGFBP-3) system. Adult male Wistar rats were either pretreated with the Kupffer cell inhibitor gadolinium chloride (10 mg/kg, i.v., 24 h prior to LPS exposure) or saline vehicle. Rats received two i.p. injections of 1 mg/kg LPS (at 17:30 and 08:30 h the following day) and were killed 4 h after the second injection. LPS administration induced a significant decrease in body weight and in serum concentrations of IGF-I and IGFBP-3 (P < 0.01), as well as in their gene expression in the liver. LPS-injected rats had increased serum concentrations of ACTH, corticosterone (P < 0.05), tumour necrosis factor-alpha (TNF-alpha) and nitrites (P < 0.01). Pretreatment of the animals with gadolinium chloride blocked the inhibitory effect of LPS on body weight, and on serum concentrations of IGF-I, IGFBP-3 and nitrites, as well as growth hormone receptor (GHR), IGF-I and IGFBP-3 gene expression in the liver. In contrast, gadolinium chloride administration did not modify the stimulatory effect of LPS on serum concentrations of ACTH, corticosterone and TNF-alpha. These results suggest that Kupffer cells are important mediators in the inhibitory effect of LPS on GHR, IGF-I and IGFBP-3 gene expression in the liver, leading to a decrease in serum concentrations of IGF-I and IGFBP-3.chemLIPOPOLYSACCHARIDESchemGADOLINIUM CHLORIDEdiseaseWEIGHT LOSSgeneIGF1geneTNFgeneIGFBP3genePOMCaction termexpressionaction termreactionixnLipopolysaccharides results in decreased expression of IGF1 proteinixngadolinium chloride inhibits the reaction [Lipopolysaccharides results in decreased expression of IGFBP3 protein]ixnLipopolysaccharides results in increased expression of POMC proteinixngadolinium chloride does not affect the reaction [Lipopolysaccharides results in increased expression of POMC protein]ixnLipopolysaccharides results in decreased expression of IGFBP3 proteinixngadolinium chloride does not affect the reaction [Lipopolysaccharides results in increased expression of TNF protein]ixngadolinium chloride has a real or putative therapeutic role towards Weight LossixnLipopolysaccharides plays a role in or acts as a marker for Weight Lossixngadolinium chloride inhibits the reaction [Lipopolysaccharides results in decreased expression of IGF1 protein]22029500title0Resveratrol abrogates adhesion molecules and protects against TNBS-induced ulcerative colitis in rats.abstract103Resveratrol, a polyphenol compound with anti-inflammatory properties, has been previously evaluated for its beneficial effects in several ulcerative colitis models. However, the current study elucidates the effect of resveratrol on adhesion molecules, as well as its antioxidant efficacy in a trinitrobenzene sulfonic acid (TNBS)-induced ulcerative-colitis model. Colitis was induced by rectal instillation of TNBS, followed by daily per os administration of either sulphasalazine (300 mg/kg) or resveratrol (2 and 10 mg/kg) for 7 days. Administration of resveratrol decreased the ulcerative area and colon mass index; these effects were further supported by the reduction in colon inflammation grades, as well as histolopathological changes, and reflected by the stalling of body mass loss. The anti-inflammatory effects of resveratrol were indicated by lowered myeloperoxidase activity, and by suppressing ICAM-1 and VCAM-1 levels in the colon and serum. In addition, it restored a reduced colonic nitric oxide level and reinstated its redox balance, as evidenced by the suppression of lipid peroxides and prevention of glutathione depletion. The anti-ulcerative effect of the higher dose of resveratrol was comparable with those of sulphasalazine. The study confirms the anti-ulcerative effect of resveratrol in TNBS-induced experimental colitis via reduction of neutrophil infiltration, inhibition of adhesive molecules, and restoration of the nitric oxide level, as well as the redox status.chemTRINITROBENZENESULFONIC ACIDchemRESVERATROLdiseaseCOLITISdiseaseINFLAMMATIONgeneICAM1geneMPOgeneVCAM1action termreactionaction termexpressionaction termactivityixnresveratrol has a real or putative therapeutic role towards Inflammationixnresveratrol plays a role in or acts as a marker for ColitisixnTrinitrobenzenesulfonic Acid plays a role in or acts as a marker for ColitisixnTrinitrobenzenesulfonic Acid results in increased expression of VCAM1 proteinixnTrinitrobenzenesulfonic Acid results in increased expression of ICAM1 proteinixnresveratrol inhibits the reaction [Trinitrobenzenesulfonic Acid results in increased expression of ICAM1 protein]ixnresveratrol inhibits the reaction [Trinitrobenzenesulfonic Acid results in increased expression of VCAM1 protein]ixnTrinitrobenzenesulfonic Acid results in increased activity of MPO proteinixnresveratrol inhibits the reaction [Trinitrobenzenesulfonic Acid results in increased activity of MPO protein]20810785title0Effects of selenite and chelating agents on mammalian thioredoxin reductase inhibited by mercury: implications for treatment of mercury poisoning.abstract147Mercury toxicity is a highly interesting topic in biomedicine due to the severe endpoints and treatment limitations. Selenite serves as an antagonist of mercury toxicity, but the molecular mechanism of detoxification is not clear. Inhibition of the selenoenzyme thioredoxin reductase (TrxR) is a suggested mechanism of toxicity. Here, we demonstrated enhanced inhibition of activity by inorganic and organic mercury compounds in NADPH-reduced TrxR, consistent with binding of mercury also to the active site selenolthiol. On treatment with 5 M selenite and NADPH, TrxR inactivated by HgCl(2) displayed almost full recovery of activity. Structural analysis indicated that mercury was complexed with TrxR, but enzyme-generated selenide removed mercury as mercury selenide, regenerating the active site selenocysteine and cysteine residues required for activity. The antagonistic effects on TrxR inhibition were extended to endogenous antioxidants, such as GSH, and clinically used exogenous chelating agents BAL, DMPS, DMSA, and -lipoic acid. Consistent with the in vitro results, recovery of TrxR activity and cell viability by selenite was observed in HgCl(2)-treated HEK 293 cells. These results stress the role of TrxR as a target of mercurials and provide the mechanism of selenite as a detoxification agent for mercury poisoning.chemMETHYLMERCURIC CHLORIDEchemSODIUM SELENITEchemDIMETHYL MERCAPTOSUCCINATEchemDIMERCAPROLchemUNITHIOLchemMERCURIC CHLORIDEchemNADPchemTHIOCTIC ACIDdiseaseMERCURY POISONINGgeneTXNRD1action termreactionaction termcotreatmentaction termactivityixnMercuric Chloride results in decreased activity of TXNRD1 proteinixnSodium Selenite has a real or putative therapeutic role towards Mercury Poisoningixnmethylmercuric chloride results in decreased activity of TXNRD1 proteinixndimethyl mercaptosuccinate inhibits the reaction [Mercuric Chloride results in decreased activity of TXNRD1 protein]ixn[Sodium Selenite co-treated with NADP] inhibits the reaction [Mercuric Chloride results in decreased activity of TXNRD1 protein]ixnDimercaprol inhibits the reaction [Mercuric Chloride results in decreased activity of TXNRD1 protein]ixnUnithiol inhibits the reaction [Mercuric Chloride results in decreased activity of TXNRD1 protein]ixnThioctic Acid inhibits the reaction [Mercuric Chloride results in decreased activity of TXNRD1 protein]ixnMercuric Chloride results in decreased activity of TXNRD1 proteinixnSodium Selenite inhibits the reaction [Mercuric Chloride results in decreased activity of TXNRD1 protein]18471454title0Comparison of the safety and efficacy of a combination tablet of niacin extended release and simvastatin vs simvastatin monotherapy in patients with increased non-HDL cholesterol (from the SEACOAST I study).abstract208The efficacy and safety of 2 regimens of a combination of a proprietary niacin extended release plus simvastatin (NER/S; 1,000/20 and 2,000/20 mg/day) were compared with simvastatin monotherapy (20 mg/day) for 24 weeks in 319 high-risk patients with predominantly mixed dyslipidemia who were already at National Cholesterol Education Program Adult Treatment Panel III risk-adjusted goals for low-density lipoprotein cholesterol. After a run-in on simvastatin 20 mg/day, both NER/S doses (1,000/20 and 2,000/20 mg/day) resulted in greater decreases in non-high-density lipoprotein (HDL) cholesterol vs simvastatin 20 mg/day (-13.9% and -22.5% vs -7.4%, respectively; p <0.01). Significant improvements in HDL cholesterol, triglycerides, apolipoprotein B, lipoprotein(a), and total/HDL cholesterol ratio were also observed. Patients with hypertriglyceridemia (triglycerides > or =200 mg/dl) typically had greater lipid responses to NER/S with the notable exception that HDL cholesterol responses to NER/S were similar in those with or without increased triglycerides. Treatment with both doses of NER/S was well tolerated; < or =60% of patients in any treatment group experienced flushing, >90% of flushing was mild or moderate in intensity, and only 7.5% of patients in both NER/S treatment groups discontinued because of flushing. The safety of NER/S was consistent with the safety profile of each individual component. In conclusion, this study showed that NER/S provided additional clinically relevant improvements in multiple lipid parameters and was safe and well tolerated.chemNIACINchemSIMVASTATINdiseaseHYPERTRIGLYCERIDEMIAdiseaseHYPERCHOLESTEROLEMIAdiseaseDYSLIPIDEMIASdiseaseFLUSHINGgeneLPAgeneAPOBaction termexpressionaction termcotreatmentixnNiacin has a real or putative therapeutic role towards HypercholesterolemiaixnNiacin has a real or putative therapeutic role towards HypertriglyceridemiaixnSimvastatin has a real or putative therapeutic role towards HypercholesterolemiaixnSimvastatin has a real or putative therapeutic role towards DyslipidemiasixnNiacin has a real or putative therapeutic role towards DyslipidemiasixnSimvastatin has a real or putative therapeutic role towards Hypertriglyceridemiaixn[Niacin co-treated with Simvastatin] results in decreased expression of LPA proteinixn[Niacin co-treated with Simvastatin] results in decreased expression of APOB proteinixnNiacin plays a role in or acts as a marker for Flushing17993463title0Tetranor PGDM, an abundant urinary metabolite reflects biosynthesis of prostaglandin D2 in mice and humans.abstract108Prostaglandin D(2) (PGD(2)) is a cyclooxygenase (COX) product of arachidonic acid that activates D prostanoid receptors to modulate vascular, platelet, and leukocyte function in vitro. However, little is known about its enzymatic origin or its formation in vivo in cardiovascular or inflammatory disease. 11,15-dioxo-9alpha-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor PGDM) was identified by mass spectrometry as a metabolite of infused PGD(2) that is detectable in mouse and human urine. Using liquid chromatography-tandem mass spectrometry, tetranor PGDM was much more abundant than the PGD(2) metabolites, 11beta-PGF(2alpha) and 2,3-dinor-11beta-PGF(2alpha), in human urine and was the only endogenous metabolite detectable in mouse urine. Infusion of PGD(2) dose dependently increased urinary tetranor PGDM > 2,3-dinor-11beta-PGF(2alpha) > 11beta-PGF(2alpha) in mice. Deletion of either lipocalin-type or hemopoietic PGD synthase enzymes decreased urinary tetranor PGDM. Deletion or knockdown of COX-1, but not deletion of COX-2, decreased urinary tetranor PGDM in mice. Correspondingly, both PGDM and 2,3-dinor-11beta-PGF(2alpha) were suppressed by inhibition of COX-1 and COX-2, but not by selective inhibition of COX-2 in humans. PGD(2) has been implicated in both the development and resolution of inflammation. Administration of bacterial lipopolysaccharide coordinately elevated tetranor PGDM and 2,3-dinor-11beta-PGF(2alpha) in volunteers, coincident with a pyrexial and systemic inflammatory response, but both metabolites fell during the resolution phase. Niacin increased tetranor PGDM and 2,3-dinor-11beta-PGF(2alpha) in humans coincident with facial flushing. Tetranor PGDM is an abundant metabolite in urine that reflects modulated biosynthesis of PGD(2) in humans and mice.chemNIACINchem11,15-DIOXO-9-HYDROXY-2,3,4,5-TETRANORPROSTAN-1,20-DIOIC ACIDchemLIPOPOLYSACCHARIDESchemF2-ISOPROSTANESdiseaseINFLAMMATIONdiseaseFLUSHINGgenePTGDSgeneHPGDSgenePTGS2genePTGS1action termabundanceixnNiacin plays a role in or acts as a marker for FlushingixnPTGS2 protein does not affect the abundance of 11,15-dioxo-9-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acidixnLipopolysaccharides plays a role in or acts as a marker for Inflammationixn11,15-dioxo-9-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid plays a role in or acts as a marker for InflammationixnPTGS1 protein results in increased abundance of 11,15-dioxo-9-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acidixnPTGS1 protein results in increased abundance of 11,15-dioxo-9-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acidixnPTGDS protein results in increased abundance of 11,15-dioxo-9-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acidixnHPGDS protein results in increased abundance of 11,15-dioxo-9-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acidixnPTGS2 protein does not affect the abundance of 11,15-dioxo-9-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acidixnF2-Isoprostanes plays a role in or acts as a marker for Inflammation19277604title0n-3 fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet.abstract157AIMS/HYPOTHESIS: Fatty acids of marine origin, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) act as hypolipidaemics, but they do not improve glycaemic control in obese and diabetic patients. Thiazolidinediones like rosiglitazone are specific activators of peroxisome proliferator-activated receptor gamma, which improve whole-body insulin sensitivity. We hypothesised that a combined treatment with a DHA and EPA concentrate (DHA/EPA) and rosiglitazone would correct, by complementary additive mechanisms, impairments of lipid and glucose homeostasis in obesity.
METHODS: Male C57BL/6 mice were fed a corn oil-based high-fat diet. The effects of DHA/EPA (replacing 15% dietary lipids), rosiglitazone (10 mg/kg diet) or a combination of both on body weight, adiposity, metabolic markers and adiponectin in plasma, as well as on liver and muscle gene expression and metabolism were analysed. Euglycaemic-hyperinsulinaemic clamps were used to characterise the changes in insulin sensitivity. The effects of the treatments were also analysed in dietary obese mice with impaired glucose tolerance (IGT).
RESULTS: DHA/EPA and rosiglitazone exerted additive effects in prevention of obesity, adipocyte hypertrophy, low-grade adipose tissue inflammation, dyslipidaemia and insulin resistance, while inducing adiponectin, suppressing hepatic lipogenesis and decreasing muscle ceramide concentration. The improvement in glucose tolerance reflected a synergistic stimulatory effect of the combined treatment on muscle glycogen synthesis and its sensitivity to insulin. The combination treatment also reversed dietary obesity, dyslipidaemia and IGT.
CONCLUSIONS/INTERPRETATION: DHA/EPA and rosiglitazone can be used as complementary therapies to counteract dyslipidaemia and insulin resistance. The combination treatment may reduce dose requirements and hence the incidence of adverse side effects of thiazolidinedione therapy.chemROSIGLITAZONEchemDOCOSAHEXAENOIC ACIDSchemEICOSAPENTAENOIC ACIDdiseaseDYSLIPIDEMIASdiseaseINSULIN RESISTANCEdiseaseGLUCOSE INTOLERANCEgenePPARGaction termactivityixnEicosapentaenoic Acid has a real or putative therapeutic role towards DyslipidemiasixnDocosahexaenoic Acids has a real or putative therapeutic role towards Dyslipidemiasixnrosiglitazone has a real or putative therapeutic role towards Insulin Resistanceixnrosiglitazone results in increased activity of PPARG proteinixnEicosapentaenoic Acid has a real or putative therapeutic role towards Insulin ResistanceixnDocosahexaenoic Acids has a real or putative therapeutic role towards Glucose IntoleranceixnDocosahexaenoic Acids has a real or putative therapeutic role towards Insulin Resistanceixnrosiglitazone has a real or putative therapeutic role towards Glucose Intoleranceixnrosiglitazone has a real or putative therapeutic role towards DyslipidemiasixnEicosapentaenoic Acid has a real or putative therapeutic role towards Glucose Intolerance12352873title0Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1.abstract168Today, the major problem in organ transplantation is not acute graft rejection but chronic graft deterioration. In addition to alloantigen-specific events, alloantigen independent factors like donor age, previous diseases, consequences of brain death, and perioperative events of ischemia/reperfusion injury have a major impact on long-term graft function. The induction of the stress protein heme oxygenase-1 (HO-1) protects cells from injury and apoptosis. Here, we tested the protective effects of HO-1 induction in a clinically relevant kidney transplant model. Induction of HO-1 expression following cobalt-protoporphyrin (CoPP) treatment in organ donors prolonged graft survival and long-term function remarkably following extended periods of ischemia. Positive effects were observed with both optimal and marginal grafts from old donor animals. Structural changes characteristic for chronic rejection, as well as graft infiltration by monocytes/macrophages and CD8+ T cells, were substantially reduced following HO-1 induction. Up-regulation of HO-1 expression before organ transplantation was also associated with reduced levels for tumor necrosis factor (TNF)-alpha mRNA, increased levels for interferon (IFN)-gamma, and bcl-x, and insignificant differences for CD25, interleukin (IL)-2, IL-4, IL-6, and IL-10 mRNA levels. The significant improvement of long-term graft function following induction of HO-1 expression in donor organs suggests that this strategy may be a novel clinical treatment option with particular relevance for transplantation of marginal organs.chemCOBALTIPROTOPORPHYRINchemZINC PROTOPORPHYRINdiseaseREPERFUSION INJURYgeneBCL2L1geneHMOX1geneTNFgeneIFNGaction termreactionaction termexpressionaction termactivityixn[cobaltiprotoporphyrin results in increased expression of HMOX1 protein] which results in increased expression of BCL2L1 mRNAixncobaltiprotoporphyrin results in increased expression of HMOX1 proteinixncobaltiprotoporphyrin results in increased activity of HMOX1 proteinixnzinc protoporphyrin results in decreased expression of HMOX1 proteinixnHMOX1 has a real or putative therapeutic role towards Reperfusion Injuryixnzinc protoporphyrin inhibits the reaction [cobaltiprotoporphyrin results in increased expression of HMOX1 protein]ixncobaltiprotoporphyrin has a real or putative therapeutic role towards Reperfusion Injuryixn[cobaltiprotoporphyrin results in increased expression of HMOX1 protein] which results in decreased expression of TNF mRNAixn[cobaltiprotoporphyrin results in increased expression of HMOX1 protein] which results in increased expression of IFNG mRNA18853145title0Effects of pantoprazole on ulcer healing delay associated with NSAID treatment.abstract80Nonsteroidal anti-inflammatory drugs delay gastric ulcer healing, and the ability of proton pump inhibitors to counteract this detrimental effect is debated. This study evaluates the effects of pantoprazole on experimental gastric ulcer healing in the presence of indomethacin. Rats with acetic-acid-induced gastric ulcers were orally treated for 3 or 7 days with pantoprazole (15 micromol/kg/day) or famotidine (20 micromol/kg/day), alone or in combination with indomethacin (3 micromol/kg/day). Ulcerated tissues were processed to assess ulcer area, malondialdehyde, proliferating cell nuclear antigen (PCNA) and cleaved caspase-3. Experiments on pylorus-ligated rats indicated that pantoprazole and famotidine were employed at equivalent inhibitory doses on gastric acid secretion (-67.9% and -64.5%, respectively). Indomethacin delayed ulcer healing both at days 3 and 7 (+22 and +35 mm(2) vs control ulcer, respectively). At day 3, pantoprazole was more effective than famotidine in promoting ulcer healing in indomethacin-treated animals (-53.6 and -31.6 mm(2) vs indomethacin, respectively). Malondialdehyde levels and caspase-3 activation in ulcers were increased by indomethacin (+79% and +3.7 folds vs control ulcer, respectively), and these effects were counteracted by pantoprazole (-77.9% and -3.5 folds vs indomethacin, respectively), but not famotidine. Increments of ulcer PCNA expression (+2.5 folds vs normal) were enhanced further by pantoprazole or famotidine, alone or in combination with indomethacin (+8.6 and +10.3 folds vs normal, respectively). Similar results were obtained after 7-day treatments of ulcerated animals with test drugs. It is concluded that, along with acid suppression, pantoprazole exerts acid-independent effects on ulcer healing, which can be ascribed to a decrease in tissue oxidation and apoptosis.chemACETIC ACIDchemPANTOPRAZOLEchemFAMOTIDINEchemINDOMETHACINdiseaseSTOMACH ULCERgenePCNAgeneCASP3action termexpressionaction termreactionaction termcotreatmentaction termactivityixnFamotidine has a real or putative therapeutic role towards Stomach UlcerixnFamotidine promotes the reaction [Acetic Acid results in increased expression of PCNA protein]ixnAcetic Acid plays a role in or acts as a marker for Stomach Ulcerixn[pantoprazole co-treated with Indomethacin] promotes the reaction [Acetic Acid results in increased expression of PCNA protein]ixnpantoprazole has a real or putative therapeutic role towards Stomach UlcerixnIndomethacin results in increased activity of CASP3 proteinixnAcetic Acid results in increased expression of PCNA proteinixnpantoprazole promotes the reaction [Acetic Acid results in increased expression of PCNA protein]ixn[Famotidine co-treated with Indomethacin] promotes the reaction [Acetic Acid results in increased expression of PCNA protein]ixnpantoprazole inhibits the reaction [Indomethacin results in increased activity of CASP3 protein]17089059title0Inhibitory effects of Hochu-ekki-to on endometrial carcinogenesis induced by N-methyl-N-nitrosourea and 17beta-estradiol in mice.abstract130An evaluation of the effects of a traditional Chinese herbal medicine, Hochu-ekki-to (Bu-zong-yi-qi-tang) on endometrial carcinogenesis was performed in experiments with female mice. In the short-term experiment, dietary exposure of Hochu-ekki-to (0.2% for 2 weeks) decreased the estradiol-17beta (E2)-stimulated expression levels of c-jun (P<0.001), tumor necrosis factor (TNF)-alpha (P<0.005), estrogen receptors (ER)-alpha (P<0.001) and ER-beta (P<0.005), as determined by reverse transcription-polymerase chain reaction and a Southern blot analysis in the uteri of the ovarectomized mice. In the long-term experiment, the mice were given N-methyl-N-nitrosourea (MNU) solution (1 mg/100 g body weight) and normal saline (as controls) into their left and right uterine corpora, respectively, and then were divided into four groups. Group 1 (25 mice) was given a diet with Hochu-ekki-to and 5 ppm E2. Group 2 (25 mice) was given a diet with E2 alone. Group 3 (25 mice) was given a diet with Hochu-ekki-to alone. Group 4 (25 mice) was kept on the basal diet alone and treated as a control. The incidence of uterine endometrial cancer in the group with Hochu-ekki-to treatment was substantially lower than of the control group. The inhibitory effect of Hochu-ekki-to on endometrial carcinogenesis is thus suggested to decrease the expressions of c-jun, TNF-alpha, ER-alpha and -beta.chemESTRADIOLchemBU-ZHONG-YI-QI-TANGdiseaseENDOMETRIAL NEOPLASMSgeneESR2geneESR1geneTNFgeneJUNaction termreactionaction termexpressionixnbu-zhong-yi-qi-tang has a real or putative therapeutic role towards Endometrial Neoplasmsixnbu-zhong-yi-qi-tang inhibits the reaction [Estradiol results in increased expression of JUN mRNA]ixnbu-zhong-yi-qi-tang inhibits the reaction [Estradiol results in increased expression of ESR2 mRNA]ixnbu-zhong-yi-qi-tang inhibits the reaction [Estradiol results in increased expression of TNF mRNA]ixnbu-zhong-yi-qi-tang inhibits the reaction [Estradiol results in increased expression of ESR1 mRNA]ixnEstradiol results in increased expression of JUN mRNAixnEstradiol results in increased expression of TNF mRNAixnEstradiol results in increased expression of ESR1 mRNAixnEstradiol results in increased expression of ESR2 mRNA19387321title0A phosphodiesterase III inhibitor protects rat liver from sinusoidal obstruction syndrome through heme oxygenase-1 induction.abstract126OBJECTIVE: The aim of study was to investigate pharmacological treatment for sinusoidal obstruction syndrome (SOS).
BACKGROUND: SOS is associated with oxaliplatin-based chemotherapy in patients with hepatic colorectal metastases. Patients with SOS have increased postoperative morbidity after major hepatectomy, but a method for effective prevention of SOS has not been established.
METHODS: Male Sprague-Dawley rats were treated with cobalt protoporphyrin IX (CoPP) or olprinone (OLP), a phosphodiesterase III inhibitor, and hepatic HO-1 expression and HO enzymatic activity were determined. Monocrotaline (MCT) was given to rats to induce SOS, and blockage of SOS by CoPP or OLP-induced hepatic HO-1 was examined in these rats. Zinc protoporphyrin IX (ZnPP), a competitive HO inhibitor, was given to MCT-treated rats together with OLP to clarify the mechanism of protection against SOS. We also examined if OLP preserved remnant liver function after 70% hepatectomy in MCT-treated rats.
RESULTS: OLP up-regulated hepatic HO-1 protein expression and HO enzymatic activity, and activated Akt protein. Administration of ZnPP to OLP-treated rats resulted in inhibition of HO activity and inactivation of Akt. Induction of HO-1 by pretreatment with CoPP led to amelioration of SOS in histologic findings and blockage of elevation of serum liver enzymes. Pretreatment with OLP gave a similar result and preserved remnant liver function, as indicated by improved survival after hepatectomy. ZnPP completely abolished the protective effects of OLP.
CONCLUSIONS: Protection of the liver from drug-induced injury by prior up-regulation of HO-1 using OLP may have potential as a therapeutic strategy for prevention of SOS.chemMONOCROTALINEchemOXALIPLATINchemZINC PROTOPORPHYRINchemCOBALTIPROTOPORPHYRINchemOLPRINONEdiseaseHEPATIC VENO-OCCLUSIVE DISEASEgeneAKT1geneHMOX1action termreactionaction termexpressionaction termactivityixncobaltiprotoporphyrin results in increased expression of HMOX1 proteinixnoxaliplatin plays a role in or acts as a marker for Hepatic Veno-Occlusive DiseaseixnMonocrotaline plays a role in or acts as a marker for Hepatic Veno-Occlusive Diseaseixncobaltiprotoporphyrin has a real or putative therapeutic role towards Hepatic Veno-Occlusive Diseaseixnolprinone has a real or putative therapeutic role towards Hepatic Veno-Occlusive Diseaseixnolprinone results in increased expression of and results in increased activity of HMOX1 proteinixnolprinone results in increased activity of AKT1 proteinixnzinc protoporphyrin inhibits the reaction [olprinone results in increased activity of AKT1 protein]ixnzinc protoporphyrin inhibits the reaction [olprinone results in increased activity of HMOX1 protein]14632209title0Arsenic trioxide induces apoptosis of cutaneous T cell lymphoma cells: evidence for a partially caspase-independent pathway and potentiation by ascorbic acid (vitamin C).abstract171Arsenic trioxide (As2O3) displays apoptogenic properties against various types of hematopoietic malignancies. We investigated the effects of As2O3 on the viability of the cutaneous T cell lymphoma cell lines HuT-78, SeAx, and Myla, and of peripheral blood mononuclear cells from patients with S zary syndrome, by using propidium iodide and annexin-V staining, terminal deoxyuridine triphosphate nick end labeling (TUNEL), cell cycle analysis, mitochondrial transmembrane potential (delta psi(m)) alterations, cytochrome c release, and detection of processed caspase-3. We also report in vivo effects of As2O3 in two patients with cutaneous T cell lymphoma. The results show that As2O3 induces apoptosis of cutaneous T cell lymphoma lines and of S zary cells from patients in a time- and concentration-dependent manner in vitro, as demonstrated by annexin-V staining, mitochondrial depolarization, and DNA fragmentation. Ascorbic acid 100 microM potentiated As2O3-induced S zary cell death, whereas interferon-alpha had no synergistic effect. As2O3-induced S zary cell death involves activation of caspase-3, cleavage of poly(ADP-ribose)polymerase, and cytochrome c release, but was only partially inhibited by the pancaspase inhibitor Z-VAD.fluoromethylketone. Finally, As2O3 was administered to two patients with cutaneous T cell lymphoma, allowing us to obtain a partial response in one case, whereas stability was observed in the second patient. These results demonstrate that As2O3 synergizes with ascorbic acid to induce S zary cell death at clinically achievable concentrations, through a caspase-partially independent pathway, and provide a rationale for further in vivo studies addressing the therapeutic efficacy of As2O3 in cutaneous T cell lymphoma patients.chemASCORBIC ACIDchemARSENIC TRIOXIDEdiseaseLYMPHOMA, T-CELL, CUTANEOUSgeneCASP3genePARP1action termcleavageaction termactivityixnarsenic trioxide results in increased cleavage of PARP1 proteinixnarsenic trioxide results in increased activity of CASP3 proteinixnarsenic trioxide has a real or putative therapeutic role towards Lymphoma, T-Cell, Cutaneous20621845title0Elevation of ADAM10, ADAM17, MMP-2 and MMP-9 expression with media degeneration features CaCl2-induced thoracic aortic aneurysm in a rat model.abstract144PURPOSE: This study was designed to establish a rat model of thoracic aortic aneurysm (TAA) by calcium chloride (CaCl(2))-induced arterial injury and to explore the potential role of a disintegrin and metalloproteinase (ADAM), matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) in TAA formation.
METHODS: Thoracic aorta of male Sprague-Dawley rats was exposed to 0.5M CaCl(2) or normal saline (NaCl). After 12weeks, animals were euthanized, and CaCl(2)-treated, CaCl(2)-untreated (n=12) and NaCl-treated aortic segments (n=12) were collected for histological and molecular assessments. MMP-TIMP and ADAM mRNAs were semi-quantitatively analyzed and protein expressions were determined by immunohistochemistry.
RESULTS: Despite similar external diameters among CaCl(2)-treated, non-CaCl(2)-treated and NaCl-treated segments, aneurymal alteration (n=6, 50%), media degeneration with regional disruption, fragmentation of elastic fiber, and increased collagen deposition (n=12, 100%) were demonstrated in CaCl(2)-treated segments. MMP-2, MMP-9, ADAM-10 and ADAM-17 mRNA levels were increased in CaCl(2)-treated segments (all p<0.01), with trends of elevation in CaCl(2)-untreated segments, as compared with NaCl-treated segments. Immunohistochemistry displayed significantly increased expressions of MMP-2, MMP-9, ADAM-10 and ADAM-17 (all p<0.01) in intima and media for CaCl(2)-treated segments. TIMP mRNA and tissue levels did not differ obviously among the three aortic segments.
CONCLUSION: This study establishes a TAA model by periarterial CaCl(2) exposure in rats, and demonstrates a significant elevation of expression of MMP-2, MMP-9, ADAM10 and ADAM17 in the pathogenesis of vascular remodeling.chemCALCIUM CHLORIDEdiseaseAORTIC ANEURYSM, THORACICgeneADAM17geneADAM10geneMMP9geneMMP2action termexpressionixnCalcium Chloride results in increased expression of MMP2 mRNAixnCalcium Chloride results in increased expression of MMP9 mRNAixnCalcium Chloride results in increased expression of ADAM10 proteinixnCalcium Chloride results in increased expression of ADAM17 proteinixnCalcium Chloride plays a role in or acts as a marker for Aortic Aneurysm, ThoracicixnCalcium Chloride results in increased expression of ADAM10 mRNAixnCalcium Chloride results in increased expression of MMP2 proteinixnCalcium Chloride results in increased expression of ADAM17 mRNAixnCalcium Chloride results in increased expression of MMP9 protein10646786title0Administration of antenatal glucocorticoids upregulates peptide growth factor gene expression in nitrofen-induced congenital diaphragmatic hernia in rats.abstract155BACKGROUND/PURPOSE: There is increasing evidence to suggest that various growth factors play a crucial role in fetal lung growth and morphogenesis. An array of peptide growth factors regulate cell proliferation, differentiation, and various other cell functions in the developing lung. The aim of this study was to investigate the effect of antenatal glucocorticoids administration on gene expression of basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta1 in nitrofen-induced congenital diaphragmatic hernia (CDH) in rats.
METHODS: A CDH model was induced in pregnant rats after administration of nitrofen. Dexamethasone (Dex; 0.25 mg/kg) was given intraperitoneally on day 18.5 and 19.5 of gestation (term, day 22). Cesarean section was performed on day 21 of gestation. mRNA was extracted from left lung and reverse transcription-polymerase chain reaction (RT-PCR) was performed to evaluate mRNA expression of each growth factors. Relative levels of mRNA were expressed as a ratio of the band density divided by that of beta-actin, a housekeeping gene known to be expressed at a constant level.
RESULTS: Relative mRNA levels of bFGF and TGF-beta1 were decreased significantly in CDH lung compared with controls. Antenatal Dex treatment up-regulated gene expression of bFGF, PDGF, and TGF-beta1 in the hypoplastic CDH lung.
CONCLUSIONS: The authors'' findings suggest that decreased gene expression of bFGF, PDGF, and TGF-beta1 in the CDH lung may suppress lung growth and development. Increased gene expression of bFGF, PDGF, and TGF-beta1 in Dex-treated lung suggests that antenatal glucocorticoid administration may accelerate fetal lung growth by up-regulating these growth factors.chemNITROFENchemDEXAMETHASONEdiseaseHERNIA, DIAPHRAGMATICgeneTGFB1genePDGFAgeneFGF2action termreactionaction termexpressionixnnitrofen plays a role in or acts as a marker for Hernia, DiaphragmaticixnFGF2 plays a role in or acts as a marker for Hernia, DiaphragmaticixnTGFB1 plays a role in or acts as a marker for Hernia, DiaphragmaticixnDexamethasone inhibits the reaction [nitrofen results in decreased expression of FGF2 mRNA]ixnDexamethasone inhibits the reaction [nitrofen results in decreased expression of TGFB1 mRNA]ixnDexamethasone inhibits the reaction [nitrofen results in decreased expression of PDGFA mRNA]ixnnitrofen results in decreased expression of FGF2 mRNAixnnitrofen results in decreased expression of TGFB1 mRNAixnnitrofen results in decreased expression of PDGFA mRNA12773168title0Human carboxylesterase 1: from drug metabolism to drug discovery.abstract66Human carboxylesterase 1 (hCE1) is a serine esterase involved in both drug metabolism and activation, as well as other biological processes. hCE1 catalyses the hydrolysis of heroin and cocaine, and the transesterification of cocaine in the presence of ethanol to the toxic metabolite cocaethylene. We have determined the crystal structures of hCE1 in complex with either the cocaine analogue homatropine or the heroin analogue naloxone. These are the first structures of a human carboxylesterase, and they provide details about narcotic metabolism in humans. hCE1''s active site contains rigid and flexible pockets, explaining the enzyme''s ability to act both specifically and promiscuously. hCE1 has also been reported to contain cholesteryl ester hydrolase, fatty acyl-CoA hydrolase and acyl-CoA:cholesterol acyltransferase activities, and thus appears to be involved in cholesterol metabolism. Since the enzyme may be useful as a treatment for cocaine overdose, and may afford protection against chemical weapons like Sarin, Soman and VX gas, hCE1 could serve as both a drug and a drug target. Selective hCE1 inhibitors targeted to several sites on the enzyme may also pave the way for novel clinical tools to manage cholesterol homoeostasis in humans.chemCOCAINEchemNALOXONEchemETHANOLchemCHOLESTEROLchemHEROINchemCOCAETHYLENEchemHOMATROPINEdiseaseCOCAINE-RELATED DISORDERSdiseaseHYPERCHOLESTEROLEMIAgeneCES1action termbindingaction termhydrolysisaction termchemical synthesisaction termcotreatmentaction termmetabolic processingixnCES1 has a real or putative therapeutic role towards Cocaine-Related DisordersixnCES1 has a real or putative therapeutic role towards HypercholesterolemiaixnCES1 protein results in increased hydrolysis of Heroinixnhomatropine binds to CES1 proteinixnCES1 protein results in increased metabolism of [Cocaine co-treated with Ethanol]ixnCES1 protein results in increased chemical synthesis of cocaethyleneixnNaloxone binds to CES1 proteinixnCES1 protein results in increased hydrolysis of CocaineixnCES1 protein results in increased metabolism of Cholesterol19931517title0Increased visceral fat mass and insulin signaling in colitis-related colon carcinogenesis model mice.abstract102Leptin, a pleiotropic hormone regulating food intake and metabolism, plays an important role in the regulation of inflammation and immunity. We previously demonstrated that serum leptin levels are profoundly increased in mice which received azoxymethane (AOM) and dextran sulfate sodium (DSS) as tumor-initiator and -promoter, respectively, in a colon carcinogenesis model. In this study, we attempted to address underlying mechanism whereby leptin is up-regulated in this rodent model. Five-week-old male ICR mice were given a single intraperitoneal injection of AOM (week 0), followed by 1% DSS in drinking water for 7 days. Thereafter, the weights of visceral fats and the serum concentration of leptin were determined at week 20. Of interest, the relative epididymal fat pad and mesenteric fat weights, together with serum leptin levels in the AOM and/or DSS-treated mice were markedly increased compared to that in untreated mice. In addition, leptin protein production in epididymal fat pad with AOM/DSS-treated mice was 4.7-fold higher than that of control. Further, insulin signaling molecules, such as protein kinase B (Akt), S6, mitogen-activate protein kinase/extracellular signaling-regulated kinase 1/2, and extracellular signaling-regulated kinase 1/2, were concomitantly activated in epididymal fat of AOM/DSS-treated mice. This treatment also increased the serum insulin and IGF-1 levels. Taken together, our results suggest that higher levels of serum insulin and IGF-1 promote the insulin signaling in epididymal fat and thereby increasing serum leptin, which may play an crucial role in, not only obesity-related, but also -independent colon carcinogenesis.chemAZOXYMETHANEchemDEXTRAN SULFATEdiseaseNEOPLASMS, EXPERIMENTALdiseaseCOLONIC NEOPLASMSgeneLEPgeneMAPK1geneIGF1geneMAPK3geneRPS6action termexpressionaction termcotreatmentaction termphosphorylationixnAzoxymethane plays a role in or acts as a marker for Colonic Neoplasmsixn[Azoxymethane co-treated with Dextran Sulfate] results in increased expression of LEP mRNAixn[Azoxymethane co-treated with Dextran Sulfate] results in increased expression of LEP proteinixnDextran Sulfate plays a role in or acts as a marker for Neoplasms, ExperimentalixnDextran Sulfate plays a role in or acts as a marker for Colonic Neoplasmsixn[Azoxymethane co-treated with Dextran Sulfate] results in increased expression of IGF1 proteinixnAzoxymethane plays a role in or acts as a marker for Neoplasms, Experimentalixn[Azoxymethane co-treated with Dextran Sulfate] results in increased phosphorylation of RPS6 proteinixn[Azoxymethane co-treated with Dextran Sulfate] results in increased phosphorylation of MAPK1 proteinixn[Azoxymethane co-treated with Dextran Sulfate] results in increased phosphorylation of MAPK3 protein19652060title0Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma.abstract84PURPOSE: To investigate the efficacy and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 in patients with metastatic renal cell carcinoma (mRCC) refractory to prior therapies that included, but were not limited to, sorafenib.
PATIENTS AND METHODS: In this multicenter, open-label, phase II study, patients with sorafenib-refractory mRCC received a starting dose of axitinib 5 mg orally twice daily. A one-arm, single-stage design was used to estimate the primary end point of objective response rate (ORR), defined by RECIST (Response Evaluation Criteria in Solid Tumors). Secondary end points included safety, duration of response, progression-free survival (PFS), overall survival (OS), and patient-reported outcomes.
RESULTS: Of 62 patients recruited, 100% had received prior sorafenib, and 74.2% had received two or more prior systemic treatments. The axitinib dose was titrated to greater than 5 mg twice daily in 53.2% of patients, and 35.5% of patients had the dose modified to less than 5 mg twice daily. In 62 patients evaluable for response, the ORR was 22.6%, and the median duration of response was 17.5 months. Median PFS and OS times were 7.4 months (95% CI, 6.7 to 11.0 months) and 13.6 months (95% CI, 8.4 to 18.8 months), respectively. All-causality grade 3 to 4 adverse events included hand-foot syndrome (16.1%), fatigue (16.1%), hypertension (16.1%), dyspnea (14.5%), diarrhea (14.5%), dehydration (8.1%), and hypotension (6.5%).
CONCLUSION: Axitinib has antitumor activity in patients with mRCC refractory to prior VEGF-targeted therapy, including sorafenib. Toxicities were mild to moderate and were manageable. A randomized, phase III trial to compare axitinib with sorafenib in patients who have mRCC refractory to one prior first-line therapy regimen is underway.chemAXITINIBdiseaseHYPOTENSIONdiseaseCARCINOMA, RENAL CELLdiseaseDEHYDRATIONdiseaseDYSPNEAdiseaseDIARRHEAdiseaseHYPERTENSIONdiseaseFATIGUEgeneFLT4geneFLT1geneKDRaction termactivityixnaxitinib has a real or putative therapeutic role towards Carcinoma, Renal Cellixnaxitinib results in decreased activity of KDRixnaxitinib results in decreased activity of FLT4ixnaxitinib results in decreased activity of FLT1ixnaxitinib plays a role in or acts as a marker for Fatigueixnaxitinib plays a role in or acts as a marker for Hypertensionixnaxitinib plays a role in or acts as a marker for Dyspneaixnaxitinib plays a role in or acts as a marker for Diarrheaixnaxitinib plays a role in or acts as a marker for Dehydrationixnaxitinib plays a role in or acts as a marker for Hypotension17724024title0Leucine carboxyl methyltransferase-1 is necessary for normal progression through mitosis in mammalian cells.abstract109Protein phosphatase 2A (PP2A) is a multifunctional phosphatase that plays important roles in many cellular processes including regulation of cell cycle and apoptosis. Because PP2A is involved in so many diverse processes, it is highly regulated by both non-covalent and covalent mechanisms that are still being defined. In this study we have investigated the importance of leucine carboxyl methyltransferase-1 (LCMT-1) for PP2A methylation and cell function. We show that reduction of LCMT-1 protein levels by small hairpin RNAs causes up to a 70% reduction in PP2A methylation in HeLa cells, indicating that LCMT-1 is the major mammalian PP2A methyltransferase. In addition, LCMT-1 knockdown reduced the formation of PP2A heterotrimers containing the Balpha regulatory subunit and, in a subset of the cells, induced apoptosis, characterized by caspase activation, nuclear condensation/fragmentation, and membrane blebbing. Knockdown of the PP2A Balpha regulatory subunit induced a similar amount of apoptosis, suggesting that LCMT-1 induces apoptosis in part by disrupting the formation of PP2A(BalphaAC) heterotrimers. Treatment with a pan-caspase inhibitor partially rescued cells from apoptosis induced by LCMT-1 or Balpha knockdown. LCMT-1 knockdown cells and Balpha knockdown cells were more sensitive to the spindle-targeting drug nocodazole, suggesting that LCMT-1 and Balpha are important for spindle checkpoint. Treatment of LCMT-1 and Balpha knockdown cells with thymidine dramatically reduced cell death, presumably by blocking progression through mitosis. Consistent with these results, homozygous gene trap knock-out of LCMT-1 in mice resulted in embryonic lethality. Collectively, our results indicate that LCMT-1 is important for normal progression through mitosis and cell survival and is essential for embryonic development in mice.chemTHYMIDINEchemNOCODAZOLEdiseaseEMBRYO LOSSgenePPP2R2AgeneLCMT1action termresponse to substanceixnPPP2R2A results in decreased susceptibility to NocodazoleixnLCMT1 results in decreased susceptibility to NocodazoleixnLCMT1 plays a role in or acts as a marker for Embryo Loss19103281title0Green tea extract increases cyclophosphamide-induced teratogenesis by modulating the expression of cytochrome P-450 mRNA.abstract122The effects of green tea extract (GTE) on the fetal development and external, visceral and skeletal abnormalities induced by cyclophosphamide were investigated in rats. Pregnant rats were daily administered GTE (100mg/kg) by gavage for 7 d, from the 6th to 12th day of gestation, and intraperitoneally administered with cyclophosphamide (11mg/kg) 1h after the final treatment. On the 20th day of gestation, maternal and fetal abnormalities were determined by Cesarian section. Cyclophosphamide was found to reduce fetal and placental weights without increasing resorption or death. In addition, it induced malformations in live fetuses; 94.6%, 41.5% and 100% of the external (skull and limb defects), visceral (cleft palate and ureteric dilatation) and skeletal (acrania, vertebral/costal malformations and delayed ossification) abnormalities. When pre-treated with GTE, cyclophosphamide-induced body weight loss and abnormalities of fetuses were remarkably aggravated. Moreover, repeated treatment with GTE greatly increased mRNA expression and activity of hepatic cytochrome P-450 (CYP) 2B, which metabolizes cyclophosphamide into teratogenic acrolein and cytotoxic phosphoramide mustard, while reducing CYP3A expression (a detoxifying enzyme). The results suggest that repeated intake of GTE may aggravate cyclophosphamide-induced body weight loss and malformations of fetuses by modulating CYP2B and CYP3A.chemCYCLOPHOSPHAMIDEchemPLANT EXTRACTSdiseaseABNORMALITIES, DRUG-INDUCEDdiseaseECTRODACTYLYdiseaseMUSCULOSKELETAL ABNORMALITIESdiseaseNEURAL TUBE DEFECTSdiseaseHEMATOMAgeneCYP3AgeneCYP2B1action termexpressionaction termactivityaction termmetabolic processingixnCyclophosphamide plays a role in or acts as a marker for Abnormalities, Drug-InducedixnCYP2B1 protein affects the metabolism of CyclophosphamideixnPlant Extracts results in decreased expression of CYP3A mRNAixnPlant Extracts results in increased expression of CYP2B1 mRNAixnCyclophosphamide plays a role in or acts as a marker for EctrodactylyixnPlant Extracts results in increased activity of CYP2B1 proteinixnPlant Extracts results in decreased activity of CYP3A proteinixnCyclophosphamide plays a role in or acts as a marker for Neural Tube DefectsixnCyclophosphamide plays a role in or acts as a marker for HematomaixnCyclophosphamide plays a role in or acts as a marker for Musculoskeletal Abnormalities21040761title0Effects of MEK and DNMT inhibitors on arsenic-treated human uroepithelial cells in relation to Cyclin-D1 and p16.abstract114Arsenic compounds are well-known toxic and carcinogenic agents, and they are widely distributed throughout the earth''s crust. These compounds are associated with various human malignancies. It has been reported that there is an elevated risk of bladder cancer in an area highly contaminated with arsenic on the southwest coast of Taiwan. However, the underlying mechanisms of arsenic-associated carcinogenesis are still unclear. The cell cycle regulatory proteins are important indicators in control of cell cycle progression. Moreover, the high expression of Cyclin-D1 and loss of p16 has been associated with a worse prognosis in a variety of human cancers. Therefore, we investigated the effect of arsenic on Cyclin-D1 and p16 expression and evaluated the role of the ERK signaling pathway and DNA methylation in arsenic carcinogenesis. Our study results showed that Cyclin-D1 high expression was found in 56.3% (9/16) of urothelial carcinomas (UC) from a blackfoot disease (BFD) area and 6.3% (1/16) of UC from a non-BFD area (p=0.002). The p16 low expression in 81.2% (13/16) of UC from BFD areas was significantly lower than in non-BFD areas (25.0%; 4/16) (p=0.001). In addition, the Cyclin-D1 increased expression but decreased p16 expression in arsenite-treated SV-HUC-1 cells. However, when cells were pretreated with inhibitors (5-aza-CdR or U0126), the effects of arsenite on Cyclin-D1 and p16 expression were suppressed. Finally, these results indicated that Cyclin-D1 and p16 both might play important roles in carcinogenesis as a result of arsenic.chemARSENITEchemDECITABINEchemU 0126diseaseUROLOGIC NEOPLASMSgeneCDKN2AgeneCCND1action termmethylationaction termreactionaction termexpressionixnarsenite results in increased expression of CCND1 proteinixnCCND1 plays a role in or acts as a marker for Urologic Neoplasmsixnarsenite results in decreased expression of CDKN2A proteinixndecitabine inhibits the reaction [arsenite results in increased expression of CCND1 protein]ixnU 0126 inhibits the reaction [arsenite results in increased expression of CCND1 protein]ixndecitabine inhibits the reaction [arsenite results in decreased expression of CDKN2A protein]ixnU 0126 inhibits the reaction [arsenite results in decreased expression of CDKN2A protein]ixnarsenite results in decreased expression of CDKN2A mRNAixnarsenite results in increased methylation of CDKN2A gene15114628title01-Benzyl-1,2,3,4-tetrahydroisoquinoline, a Parkinsonism-inducing endogenous toxin, increases alpha-synuclein expression and causes nuclear damage in human dopaminergic cells.abstract1751-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, is known to cause parkinsonism in rodents and nonhuman primates. The levels of 1BnTIQ in cerebrospinal fluid of patients with Parkinson''s disease (PD) were reported to be three times higher than those in control subjects. In the present study, we have evaluated the effects of 1BnTIQ on alpha-synuclein (alpha-syn) expression together with biochemical and morphological changes in human dopaminergic SH-SY5Y cells in culture. 1BnTIQ at lower concentrations (1-50 microM) increased alpha-syn protein expression in a time- and dose-dependent manner in these cells. There was also up-regulation of alpha-syn mRNA by 1BnTIQ. Inhibition of complex I by rotenone and depletion of glutathione by L-buthionine sulfoxamine also correlated with an increase in alpha-syn expression, suggesting that oxidative stress may cause an increase in alpha-syn levels in dopaminergic cells. Furthermore, 1BnTIQ significantly depleted glutathione levels. 1BnTIQ at higher concentrations (500 microM) increased reactive oxygen species levels, decreased ATP levels, and caused nuclear damage in the cells. The 1BnTIQ-induced alpha-syn up-regulation was inhibited by cotreatment with the antioxidants selegiline, coenzyme Q(10), and N-acetylcystein and the caspase inhibitor DEVD-CHO. Taken together, these results suggest that alpha-syn up-regulation and oxidative stress are contributing factors in 1BnTIQ-induced neurotoxicity in dopaminergic neurons in PD.chem1,2,3,4-TETRAHYDRO-1-(PHENYLMETHYL)ISOQUINOLINEchemCOENZYME Q10chemACETYLCYSTEINEchemROTENONEchemBUTHIONINE SULFOXIMINEchemACETYL-ASPARTYL-GLUTAMYL-VALYL-ASPARTALchemSELEGILINEdiseasePARKINSON DISEASEgeneSNCAaction termreactionaction termexpressionixn1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline plays a role in or acts as a marker for Parkinson DiseaseixnSelegiline inhibits the reaction [1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline results in increased expression of SNCA protein]ixncoenzyme Q10 inhibits the reaction [1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline results in increased expression of SNCA protein]ixnAcetylcysteine inhibits the reaction [1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline results in increased expression of SNCA protein]ixnacetyl-aspartyl-glutamyl-valyl-aspartal inhibits the reaction [1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline results in increased expression of SNCA protein]ixn1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline results in increased expression of SNCA proteinixn1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline results in increased expression of SNCA mRNAixnRotenone results in increased expression of SNCA proteinixnButhionine Sulfoximine results in increased expression of SNCA protein21394550title0Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats.abstract121Thrombospondin 1 (TSP-1), an antiangiogenic factor and transforming growth factor (TGF)- activity regulator, has been recently recognized as an adipokine that correlates with obesity, inflammation and insulin resistance processes. In the present study, epididymal adipocytes of rats that were fed a chow or a high-fat diet (HFD) for 50 days were isolated and incubated (24-72 h) in low (5.6 mM) or high (HG; 25 mM) glucose, in the presence or absence of 1.6 nM insulin. Rats fed the HF diet showed an established obesity state. Serum TSP-1 levels and TSP-1 mRNA basal expression of adipocytes from HFD rats were higher than those from controls. Adipocytes from HFD animals presented an insulin resistance state, as suggested by the lower insulin-stimulated glucose uptake as compared to controls. TSP-1 expression in culture was higher in adipocytes from obese animals at 24 h, but when the adipocytes were treated with HG, these expression levels dropped dramatically. Later at 72 h, TSP-1 expression was lower in adipocytes from HFD rats, and no effects of the other treatments were observed. Surprisingly, the secretion levels of this protein at 72 h were increased significantly by the HG treatment in both types of adipocytes, although they were even higher in adipocytes from obese animals. Finally, cell viability was significantly reduced by HG treatment in both types of adipocytes. In summary, TSP-1 expression/secretion was modulated in an in vitro model of insulin-resistant adipocytes. The difference between expression and secretion patterns suggests a posttranscriptional regulation. The present study confirms that TPS-1 is closely associated with obesity-related mechanisms.chemGLUCOSEchemDIETARY FATSchemLACTIC ACIDdiseaseOBESITYgeneTHBS1geneLEPgeneINS1action termreactionaction termexpressionaction termsecretionaction termuptakeixnDietary Fats results in increased expression of THBS1 proteinixnDietary Fats plays a role in or acts as a marker for ObesityixnDietary Fats affects the reaction [INS1 protein results in increased secretion of Lactic Acid]ixnDietary Fats results in increased expression of LEP mRNAixnINS1 protein results in increased uptake of GlucoseixnDietary Fats results in increased expression of THBS1 mRNAixnDietary Fats affects the reaction [INS1 protein results in increased uptake of Glucose]ixnINS1 protein results in increased secretion of Lactic AcidixnDietary Fats results in increased expression of THBS1 proteinixnGlucose inhibits the reaction [Dietary Fats results in increased expression of THBS1 protein]2947255title0The selective dopamine D2 receptor antagonist raclopride discriminates between dopamine-mediated motor functions.abstract114The actions on central dopamine (DA) mechanisms of raclopride, a new substituted benzamide, were studied by means of behavioural and biochemical methods in the rat. Raclopride blocked the in vitro binding of the dopamine D2 antagonist 3H-spiperone (IC50 = 32 nM), but not of the unselective D1 antagonist 3H-flupenthixol (IC50 greater than 100,000 nM) in rat striatum, and failed to inhibit striatal DA-sensitive adenylate cyclase in vitro (IC50 greater than 100,000 nM). Raclopride caused a dose-dependent increase in the DA metabolites HVA and DOPAC in the striatum and olfactory tubercle. Behavioural studies showed that raclopride discriminates between the motor behaviours induced by the DA agonist apomorphine. Thus, unlike haloperidol, raclopride blocked apomorphine-induced hyperactivity at considerably lower doses than those inhibiting oral stereotypies. Moreover, raclopride showed a high separation between the doses for blockade of apomorphine-induced hyperactivity and those inducing catalepsy in rats. Raclopride caused a dose-dependent blockade of the specific binding of 3H-spiperone and 3H-N-n-propylnorapomorphine (3H-NPA) in vivo at doses similar to those blocking the behavioural effects of apomorphine. The maximal blockade of 3H-spiperone binding in vivo was lower for raclopride than for haloperidol. Raclopride caused a greater inhibition of 3H-NPA than of 3H-spiperone in vivo binding in the striatum. It is suggested that the ability of raclopride to discriminate between different DA-mediated functions may be attributed to a preferential blockade of a subclass of functionally coupled dopamine D2 receptors in striatal as well as in extrastriatal brain regions in the rat.chemRACLOPRIDEchemSULPIRIDEchemSPIPERONEchemFLUPENTHIXOLchemAPOMORPHINEchemHALOPERIDOLdiseaseVOMITINGdiseaseSUBSTANCE-RELATED DISORDERSdiseaseCATALEPSYgeneDRD1AgeneDRD2action termbindingaction termactivityixnApomorphine plays a role in or acts as a marker for Substance-Related DisordersixnRaclopride has a real or putative therapeutic role towards Substance-Related DisordersixnHaloperidol has a real or putative therapeutic role towards Substance-Related DisordersixnApomorphine plays a role in or acts as a marker for VomitingixnSpiperone binds to and results in decreased activity of DRD2 proteinixnHaloperidol has a real or putative therapeutic role towards VomitingixnFlupenthixol binds to and results in decreased activity of DRD1A proteinixnRaclopride has a real or putative therapeutic role towards VomitingixnSulpiride plays a role in or acts as a marker for Catalepsy19887067title0Oral administration of the NAALADase inhibitor GPI-5693 attenuates cocaine-induced reinstatement of drug-seeking behavior in rats.abstract131We have recently reported that the endogenous mGlu2/3 agonist N-acetylaspartylglutamate (NAAG) and the N-acetylated-alpha-linked-acidic dipeptidase (NAALADase, a NAAG degradation enzyme) inhibitor 2-PMPA significantly inhibit cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior by attenuating cocaine-enhanced extracellular dopamine and glutamate in the nucleus accumbens. However, the poor oral bioavailability of NAAG and 2-PMPA limits their practical use in humans. In the present study, we investigated the effects of the orally active NAALADase inhibitor GPI-5693 and its enantiomers on cocaine-taking and cocaine-seeking behaviours. We found that oral administration of GPI-5693 (15, 30, 60 mg/kg, p.o.) did not significantly alter intravenous cocaine self-administration under fixed-ratio (FR2) reinforcement, but significantly inhibited cocaine-induced reinstatement of the extinguished drug-seeking behavior. This inhibition was blocked by pretreatment with LY341495, a selective mGlu2/3 receptor antagonist. Pretreatment with the same doses (15, 30, 60 mg/kg, p.o.) of GPI-16476 or GPI-16477, two enantiomers of GPI-5693, also inhibited cocaine-induced reinstatement similar to GPI-5693. In contrast, GPI-5693 altered neither oral sucrose self-administration nor sucrose-triggered reinstatement of sucrose-seeking behavior. These data suggest that orally effective NAAG peptidase inhibitors deserve further study as potential agents for the treatment of cocaine addiction.chemLY 341495chemN-ACETYL-1-ASPARTYLGLUTAMIC ACIDchem2-(PHOSPHONOMETHYL)PENTANEDIOIC ACIDchem2-(3-MERCAPTOPROPYL)PENTANEDIOIC ACIDdiseaseCOCAINE-RELATED DISORDERSgeneFOLH1BgeneGRM3geneGRM2action termreactionaction termbindingaction termactivityixn2-(3-mercaptopropyl)pentanedioic acid results in decreased activity of FOLH1B proteinixnLY 341495 inhibits the reaction [2-(3-mercaptopropyl)pentanedioic acid results in decreased activity of FOLH1B protein]ixn2-(3-mercaptopropyl)pentanedioic acid has a real or putative therapeutic role towards Cocaine-Related DisordersixnN-acetyl-1-aspartylglutamic acid binds to and results in increased activity of GRM2 proteinixnN-acetyl-1-aspartylglutamic acid has a real or putative therapeutic role towards Cocaine-Related Disordersixn2-(phosphonomethyl)pentanedioic acid has a real or putative therapeutic role towards Cocaine-Related DisordersixnN-acetyl-1-aspartylglutamic acid binds to and results in increased activity of GRM3 proteinixnLY 341495 binds to and results in decreased activity of GRM2 proteinixnLY 341495 binds to and results in decreased activity of GRM3 protein10614985title0Altered baroreflex control of heart rate in bradykinin B2-receptor knockout mice.abstract82Recently, we have shown that a knockout mouse strain lacking the bradykinin B2-receptor gene exhibits an accelerated heart rate (HR) under basal conditions, this alteration being associated with mildly elevated blood pressure (BP) levels and ultimately with the development of cardiomyopathy. The goal of the present study was to determine whether genetic disruption of the B2-receptor alters autonomic cardiovascular reflexes to acute or chronic changes in BP. The direct mean BP and HR levels of unrestrained B2 knockout mice (B2-/-) were higher than those of wild type (B2+/+) controls (131 +/- 2 vs. 105 +/- 2 mm Hg and 480 +/- 5 vs. 414 +/- 8 beats/min, P < 0.01 for both comparisons). The difference in HR observed between groups under basal conditions was nullified by the acute administration of propranolol and atropine as well as by hexamethonium; it was attenuated by long-term blockade of angiotensin AT1 receptors. In B2-/- mice, the presence of an alteration in baroreceptor regulation of HR was supported by a reduced gain in the HR responses to acute nitroprusside-induced hypotension or phenylephrine-induced hypertension (slope of the regression line: 0.82 +/- 0.07 vs. 5.58 +/- 0.08 beats/min per mmHg in B2+/+, P < 0.01), as well as by an exaggerated tachycardic response to chronic hypertension induced by clipping of the left renal artery (60 +/- 3 vs. 15 +/- 3 beats/min in B2+/+, P < 0.01). Our findings indicate that disruption of the bradykinin B2-receptor gene is associated with an impaired baroreflex control of HR. The combination of chronically elevated resting HR and impaired baroreflex control could contribute to the development of cardiomyopathy in these animals.chemA 81988chemHEXAMETHONIUMchemNITROPRUSSIDEchemATROPINEchemPHENYLEPHRINEchemPROPRANOLOLdiseaseHYPOTENSIONdiseaseCARDIOMYOPATHIESdiseaseHYPERTENSIONgeneBDKRB2action termcotreatmentaction termresponse to substanceixnBDKRB2 plays a role in or acts as a marker for HypertensionixnBDKRB2 affects the susceptibility to PhenylephrineixnBDKRB2 plays a role in or acts as a marker for CardiomyopathiesixnBDKRB2 affects the susceptibility to A 81988ixnNitroprusside plays a role in or acts as a marker for HypotensionixnPhenylephrine plays a role in or acts as a marker for HypertensionixnBDKRB2 affects the susceptibility to NitroprussideixnBDKRB2 affects the susceptibility to [Propranolol co-treated with Atropine]ixnBDKRB2 affects the susceptibility to Hexamethonium20156836title0Involvement of mitochondria-mediated apoptosis in ethylbenzene-induced renal toxicity in rat.abstract94Ethylbenzene is an important industrial chemical that has recently been classified as a possible human carcinogen (International Agency of Research on Cancer class 2B), but the available data do not support the genotoxic mechanism of ethylbenzene-induced tumors in kidney. We investigated the effects of ethylbenzene on renal ultrastructure and explored the nongenotoxic mechanism of mitochondria-mediated apoptosis pathway. Forty male Sprague-Dawley rats were used as a vivo model with ethylbenzene inhalation for 13 weeks, and the metabolites of ethylbenzene, mandelic acid (MA), and phenylglyoxylic acid (PGA) in urine were examined by high-performance liquid chromatography. Meanwhile, the ultrastructure of renal tubular epithelial cells was observed, and cell apoptosis was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Furthermore, we investigated the expression levels of messenger RNA (mRNA) and protein of bax, bcl-2, cytochrome c, caspase-9, and caspase-3 in rat kidney. With respect to levels of MA, PGA, and MA + PGA, a significant dose-dependent increase was observed in 4335 and 6500 mg/m(3) ethylbenzene-treated groups against the control group. The mitochondria of renal tubular epithelial cells became a compact and vacuolar structure in 6500 mg/m(3) ethylbenzene-treated group, and ethylbenzene induced a significant increase in the number of apoptotic cells as compared to the control group. In addition, enhanced mRNA and protein expression levels of all measured genes were observed in various ethylbenzene-treated groups except the decreased bcl-2 expression levels. Our results indicated that ethylbenzene may induce apoptosis of renal tubular epithelial cells via mitochondria-mediated apoptotic pathways. MA and PGA in urine might be a parameter of biological dose in vivo after ethylbenzene inhalation.chemETHYLBENZENEdiseaseACUTE KIDNEY INJURYgeneBCL2geneCASP9geneCASP3geneCYCSgeneBAXaction termexpressionixnethylbenzene results in decreased expression of BCL2 proteinixnethylbenzene plays a role in or acts as a marker for Acute Kidney Injuryixnethylbenzene results in increased expression of CASP3 mRNAixnethylbenzene results in increased expression of CYCS proteinixnethylbenzene results in increased expression of CYCS mRNAixnethylbenzene results in increased expression of BAX proteinixnethylbenzene results in decreased expression of BCL2 mRNAixnethylbenzene results in increased expression of CASP3 proteinixnethylbenzene results in increased expression of BAX mRNAixnethylbenzene results in increased expression of CASP9 protein18234736title0Motorcycle exhaust induces reproductive toxicity and testicular interleukin-6 in male rats.abstract92Motorcycle exhaust (ME) from two-stroke engines contains many toxicants and poses a potential health hazard. The major objectives of the present study were to investigate the male reproductive toxicity of ME and the underlying mechanisms of toxicity. Male Wistar rats were exposed to ME by inhalation 1 h each in the morning and afternoon, Monday through Friday. Exposures to 1:50 diluted ME for 4 weeks or to 1:10 diluted ME for 2 and 4 weeks showed concentration- and time-dependent decreases of testicular weight, spermatid number, and cauda epididymal sperm number. Subsequent studies were done using 4-week exposure to 1:10 diluted ME. ME caused histopathological changes including testicular spermatocytic necrosis and seminiferous tubule atrophy and cauda epididymal formation of clusters of pyknotic and necrotic sperm cells. ME-exposed male rats mated with untreated females showed decreases of male mating index and female fertility index and an increase of implantation site loss. ME decreased 7-ethoxycoumarin O-deethylase and superoxide dismutase activities but induced proinflammatory cytokine interleukin-6 (IL-6) messenger RNA (mRNA) in the testis. Male rats were exposed to ME with or without cotreatment with 50 mg/kg vitamin E orally for 4 weeks. ME decreased serum testosterone concentration. This effect was reversed by cotreatment with vitamin E. ME decreased testicular spermatid number and induced IL-6 mRNA and protein. These effects were also reversed by the vitamin E cotreatment. The present findings show that ME causes male reproductive effects and induces testicular IL-6 in rats by mechanisms involving induction of oxidative stress and inhibition of steroidogenesis.chemVEHICLE EMISSIONSchemVITAMIN EdiseaseGENITAL DISEASES, MALEgeneIL6geneIL1BgenePTGS2action termreactionaction termexpressionixnVehicle Emissions results in increased expression of IL6 mRNAixnVehicle Emissions plays a role in or acts as a marker for Genital Diseases, MaleixnVitamin E inhibits the reaction [Vehicle Emissions results in increased expression of IL1B mRNA]ixnVehicle Emissions results in increased expression of IL1B mRNAixnVitamin E inhibits the reaction [Vehicle Emissions results in increased expression of PTGS2 mRNA]ixnVehicle Emissions results in increased expression of PTGS2 mRNAixnVitamin E inhibits the reaction [Vehicle Emissions results in increased expression of IL6 mRNA]ixnVehicle Emissions results in increased expression of IL6 proteinixnVitamin E inhibits the reaction [Vehicle Emissions results in increased expression of IL6 protein]18245540title0WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation.abstract138PURPOSE: The discovery of an activating somatic mutation in codon 617 of the gene encoding the Janus kinase (JAK)-2 (JAK2 V617F) in patients with myeloproliferative disorders has opened new avenues for the development of targeted therapies for these malignancies. However, no effective JAK2 inhibitors are currently available for clinical use.
EXPERIMENTAL DESIGN: We investigated the activity of (E)-3(6-bromopyridin-2-yl)-2-cyano-N-(S0-1phenylethyl)acrylamide (WP1066), a novel analogue of the JAK2 inhibitor AG490, in JAK2 V617F-positive erythroleukemia HEL cells and in blood cells from patients with polycythemia vera.
RESULTS: We found that WP1066 significantly inhibited JAK2 and its downstream signal transducer and activator of transcription-3, signal transducer and activator of transcription-5, and extracellular signal-regulated kinase-1/2 pathways in a dose- and time-dependent manner. As a result, WP1066 concentrations in the low micromolar range induced time- and dose-dependent antiproliferative and proapoptotic effects in HEL cells. As expected, WP1066 inhibited the proliferation of peripheral blood hematopoietic progenitors of patients with polycythemia vera carrying the JAK2 V617F mutation in a dose-dependent manner.
CONCLUSIONS: Our data suggest that WP1066 is active both in vitro and ex vivo and should be further developed for the treatment of neoplasms expressing the JAK2 V617F mutation.chemWP1066diseasePOLYCYTHEMIA VERAdiseaseMYELOPROLIFERATIVE DISORDERSgeneSTAT5BgeneMAPK3geneMAPK1geneSTAT3genePARP1geneCASP3geneJAK2action termcleavageaction termphosphorylationaction termactivityixnWP1066 has a real or putative therapeutic role towards Myeloproliferative DisordersixnWP1066 has a real or putative therapeutic role towards Polycythemia VeraixnWP1066 results in decreased phosphorylation of JAK2 proteinixnWP1066 results in decreased phosphorylation of STAT5B proteinixnWP1066 results in decreased phosphorylation of STAT3 proteinixnWP1066 results in decreased phosphorylation of MAPK3 proteinixnWP1066 results in decreased phosphorylation of MAPK1 proteinixnWP1066 results in increased activity of CASP3 proteinixnWP1066 results in increased cleavage of PARP1 protein19225048title0Curcumin ameliorates renal failure in 5/6 nephrectomized rats: role of inflammation.abstract85TNF-alpha and NF-kappaB play important roles in the development of inflammation in chronic renal failure (CRF). In hepatic cells, curcumin is shown to antagonize TNF-alpha-elicited NF-kappaB activation. In this study, we hypothesized that if inflammation plays a key role in renal failure then curcumin should be effective in improving CRF. The effectiveness of curcumin was compared with enalapril, a compound known to ameliorate human and experimental CRF. Investigation was conducted in Sprague-Dawley rats where CRF was induced by 5/6 nephrectomy (Nx). The Nx animals were divided into untreated (Nx), curcumin-treated (curcumin), and enalapril-treated (enalapril) groups. Sham-operated animals served as a control. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was significantly reduced by curcumin and enalapril treatment. However, only enalapril significantly improved blood pressure. Compared with the control, the Nx animals had significantly higher plasma and kidney TNF-alpha, which was associated with NF-kappaB activation and macrophage infiltration in the kidney. These changes were effectively antagonized by curcumin and enalapril treatment. The decline in the anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARgamma) seen in Nx animals was also counteracted by curcumin and enalapril. Studies in mesangial cells were carried out to further establish that the anti-inflammatory effect of curcumin in vivo was mediated essentially by antagonizing TNF-alpha. Curcumin dose dependently antagonized the TNF-alpha-mediated decrease in PPARgamma and blocked transactivation of NF-kappaB and repression of PPARgamma, indicating that the anti-inflamatory property of curcumin may be responsible for alleviating CRF in Nx animals.chemCURCUMINchemENALAPRILdiseaseKIDNEY FAILURE, CHRONICgenePPARGgeneNFKB1geneTNFaction termexpressionaction termactivityixnCurcumin results in decreased activity of NFKB1 proteinixnCurcumin has a real or putative therapeutic role towards Kidney Failure, ChronicixnCurcumin results in decreased expression of TNF proteinixnCurcumin results in decreased expression of PPARG proteinixnEnalapril results in decreased activity of NFKB1 proteinixnEnalapril has a real or putative therapeutic role towards Kidney Failure, ChronicixnEnalapril results in decreased expression of TNF proteinixnEnalapril results in decreased expression of PPARG protein19747933title0Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats.abstract128Our previous work indicated that pretreatment with the selective kappa-opioid receptor (KOPr) agonist, U69593, attenuated the ability of priming injections of cocaine to reinstate extinguished cocaine-seeking behavior. The present study expanded these initial tests to include other traditional KOPr agonists, U50488H, spiradoline (SPR), and salvinorin A (Sal A), an active constituent of the plant Salvia divinorum. Following acquisition and stabilization of cocaine self-administration, cocaine-produced drug-seeking was measured. This test was conducted in a single day and comprised an initial phase of self-administration, followed by a phase of extinguished responding. The final phase examined reinstatement of extinguished cocaine self-administration followed by a priming injection of cocaine (20.0mg/kg, intraperitoneal (I.P.)) in combination with the various KOPr agonists. Cocaine-induced drug-seeking was attenuated by pretreatment with U69593 (0.3mg/kg, subcutaneous (S.C.)), U50488H (30.0mg/kg, I.P.), SPR (1.0, 3.0mg/kg, I.P.) and Sal A (0.3, 1.0mg/kg, I.P.). Sal A (0.3, 1.0mg/kg, I.P.) had no effect on operant responding to obtain sucrose reinforcement or on cocaine-induced hyperactivity. These findings show that Sal A, like other traditional KOPr agonists attenuates cocaine-induced drug-seeking behavior.chemSALVINORIN AchemU 69593chem3,4-DICHLORO-N-METHYL-N-(2-(1-PYRROLIDINYL)-CYCLOHEXYL)-BENZENEACETAMIDE, (TRANS)-ISOMERchemCOCAINEchemSPIRADOLINEdiseaseCOCAINE-RELATED DISORDERSgeneOPRK1action termbindingaction termactivityixnU 69593 binds to and results in increased activity of OPRK1 proteinixn3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer binds to and results in increased activity of OPRK1 proteinixnspiradoline binds to and results in increased activity of OPRK1 proteinixnsalvinorin A binds to and results in increased activity of OPRK1 proteinixnsalvinorin A has a real or putative therapeutic role towards Cocaine-Related Disordersixnspiradoline has a real or putative therapeutic role towards Cocaine-Related DisordersixnU 69593 has a real or putative therapeutic role towards Cocaine-Related DisordersixnCocaine plays a role in or acts as a marker for Cocaine-Related Disordersixn3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer has a real or putative therapeutic role towards Cocaine-Related Disorders12020746title0Estriol retards and stabilizes atherosclerosis through an NO-mediated system.abstract78Estriol (E3) has little effect on the female genitals. E3 is used in hormone replacement therapy, particularly in Europe and Japan, since it obviates the need for progestin administration. However, the effect of E3 on atherosclerosis has not been elucidated. In this study, we evaluated the effect of E3 on the progression of atherosclerosis in a rabbit model. Thirty-six rabbits total were used. Twenty-eight were bilaterally oophorectomized, and 8 were not. The rabbits were divided into 5 groups and treated for 12 weeks as follows. Gp I (n = 8) was fed a high cholesterol diet (HCD; standard diet plus 0.5% cholesterol); Gp II (n = 8) was fed a HCD with E3 (0.3 mg/kg/day); Gp III (n = 8) was fed a HCD with 17beta estradiol (E2) (0.1 mg/kg/day); Gp IV (n = 8), the non oophorectomized group, was fed a HCD; and Gp NC was oophorectomized (n = 4), and fed a regular diet. E3 treatment increased the plasma E2 and E3 levels in Gp II. The plasma lipid levels were not altered by the E2 or E3 treatment. A HCD diminished the acetylcholine-induced NO mediated relaxation in the thoracic aorta. The E2 treatment (Gp III) and E3 treatment (Gp II) restored the aortic basal NO release and the aortic cyclic GMP levels, particularly effectively in the E3 group. E3 treatment also decreased the atherosclerotic area, and its effect was comparable with E2 (surface involvement: 41.2 +/- 5.1% in Gp I; 10.1 +/- 2.7% in Gp II; and 6.5 +/- 1.3% in Gp III). All four hyperlipidemic groups showed an increase of eNOS mRNA in the aortae, and this was especially pronounced in Gps II and III. The level of peroxynitrite, as determined by immunohistochemical nitrotyrosine staining, was lower in Gps II and III than in Gp I. E3 strongly activates NO-mediated systems, and could play a role in retarding the progression of atherosclerosis and in stabilizing atheroma.chemCHOLESTEROLchemCHOLESTEROL, DIETARYchemESTRIOLchemESTRADIOLdiseaseHYPERLIPIDEMIASdiseaseATHEROSCLEROSISgeneNOS2geneNOS3action termexpressionaction termcotreatmentixnEstriol has a real or putative therapeutic role towards AtherosclerosisixnCholesterol, Dietary plays a role in or acts as a marker for HyperlipidemiasixnEstradiol has a real or putative therapeutic role towards AtherosclerosisixnCholesterol, Dietary plays a role in or acts as a marker for Atherosclerosisixn[Estradiol co-treated with Cholesterol] results in increased expression of NOS3 mRNAixn[Estriol co-treated with Cholesterol] results in increased expression of NOS3 mRNAixnCholesterol results in increased expression of NOS3 mRNAixn[Estradiol co-treated with Cholesterol] results in increased expression of NOS2 proteinixn[Estriol co-treated with Cholesterol] results in increased expression of NOS2 proteinixnCholesterol results in increased expression of NOS2 protein16430655title0Amplification of the urokinase gene and the sensitivity of prostate cancer cells to urokinase inhibitors.abstract106OBJECTIVES: To evaluate the frequency of the urokinase-type plasminogen activator (uPA) gene amplification and the sensitivity of prostate cancer cells to uPA inhibition, as we previously found one hormone-refractory prostate tumour with high-level amplification of the uPA (alias PLAU) gene, and also showed that a uPA inhibitor, amiloride, can effectively reduce the invasion potential of the PC-3 prostate cancer cell line.
MATERIALS AND METHODS: Sixty-three locally recurrent hormone-refractory tumours and 78 hormone-refractory metastases from 29 patients who died from prostate cancer were analysed for uPA gene-copy number using fluorescence in situ hybridization. The Matrigel invasion assay was used to study the influence of uPA inhibitors on the invasive potential of prostate cancer cell lines.
RESULTS: Of the locally recurrent hormone-refractory tumours, 21% had an increased copy number of uPA, but no high-level amplifications were found; 31% of the metastases had increased copy number and one high-level amplification of the uPA. Matrigel invasion assays with two specific uPA inhibitors, B428 and p-aminobenzamidine, showed that invasion of a prostate cancer cell line containing uPA gene amplification was inhibited by these small-molecule uPA inhibitors, while invasion of prostate cell lines without uPA gene amplification were not.
CONCLUSION: These results suggest that selective inhibition of the uPA pathway in individuals whose tumours contain uPA gene amplification may provide therapeutic benefit.chem4-IODINE-BENZO(B)THIOPHENE-2-CARBOXAMIDINEchem4-AMINOBENZAMIDINEchemAMILORIDEdiseaseNEOPLASM RECURRENCE, LOCALdiseasePROSTATIC NEOPLASMSgenePLAUaction termactivityixnPLAU plays a role in or acts as a marker for Prostatic NeoplasmsixnPLAU plays a role in or acts as a marker for Neoplasm Recurrence, Localixn4-iodine-benzo(b)thiophene-2-carboxamidine plays a role in or acts as a marker for Prostatic Neoplasmsixn4-iodine-benzo(b)thiophene-2-carboxamidine plays a role in or acts as a marker for Neoplasm Recurrence, Localixn4-aminobenzamidine plays a role in or acts as a marker for Prostatic Neoplasmsixn4-aminobenzamidine plays a role in or acts as a marker for Neoplasm Recurrence, LocalixnAmiloride results in decreased activity of PLAU proteinixn4-iodine-benzo(b)thiophene-2-carboxamidine results in decreased activity of PLAU proteinixn4-aminobenzamidine results in decreased activity of PLAU protein17145853title0Cellular FLICE-inhibitory protein down-regulation contributes to celecoxib-induced apoptosis in human lung cancer cells.abstract121The cyclooxygenase-2 (COX-2) inhibitor celecoxib is an approved drug in the clinic for colon cancer chemoprevention and has been tested for its chemopreventive and therapeutic efficacy in various clinical trials. Celecoxib induces apoptosis in a variety of human cancer cells including lung cancer cells. Our previous work has shown that celecoxib induces death receptor 5 expression, resulting in induction of apoptosis and enhancement of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. In the current study, we further show that celecoxib down-regulated the expression of cellular FLICE-inhibitory protein (c-FLIP), a major negative regulator of the death receptor-mediated extrinsic apoptotic pathway, through a ubiquitin/proteasome-dependent mechanism independent of COX-2 in human lung cancer cells. Overexpression of c-FLIP, particularly FLIP(L), inhibited not only celecoxib-induced apoptosis but also apoptosis induced by the combination of celecoxib and TRAIL. These results thus indicate that c-FLIP down-regulation also contributes to celecoxib-induced apoptosis and enhancement of TRAIL-induced apoptosis, which complements our previous finding that the extrinsic apoptotic pathway plays a critical role in celecoxib-induced apoptosis in human lung cancer cells. Collectively, we conclude that celecoxib induces apoptosis in human lung cancer cells through activation of the extrinsic apoptotic pathway, primarily by induction of death receptor 5 and down-regulation of c-FLIP.chemCELECOXIBdiseaseCOLONIC NEOPLASMSgeneTNFRSF10BgenePTGS2geneTNFSF10geneCFLARaction termreactionaction termexpressionixnPTGS2 does not affect the reaction [celecoxib results in decreased expression of CFLAR]ixncelecoxib results in decreased expression of CFLARixncelecoxib has a real or putative therapeutic role towards Colonic Neoplasmsixncelecoxib results in increased expression of TNFRSF10B19336726title0Liposomal encapsulation of deguelin: evidence for enhanced antitumor activity in tobacco carcinogen-induced and oncogenic K-ras-induced lung tumorigenesis.abstract156Deguelin has shown promising chemopreventive and therapeutic activities in diverse types of cancers. However, the potential side effect of deguelin over a certain dose could be the substantial hurdle in the practical application of the drug. One of the successful strategies for the use of deguelin in clinical trials could be lung-specific delivery of the drug. The present study evaluates the efficacy of liposome-encapsulated deguelin with a dose of 0.4 mg/kg, which is 10 times less than the dose (4 mg/kg) for preventive and therapeutic activities validated in previous in vivo studies. Liposomal deguelin revealed cytotoxic activity in vitro in premalignant and malignant human bronchial epithelial cells and non-small cell lung cancer cells through the same mechanistic pathway previously reported for deguelin (i.e., suppression of the heat shock protein 90 chaperone function and induction of apoptosis). Delivery of liposomal deguelin at a dose of 0.4 mg/kg by intranasal instillation resulted in markedly increased drug partitioning to the lungs compared with that of 4 mg/kg deguelin or 0.4 mg/kg liposomal deguelin administered by oral gavage. Lung-specific delivery of deguelin (0.4 mg/kg) via nasal or intratracheal instillation in a liposomal formulation also showed significant chemopreventive and therapeutic activities in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone/benzo(a)pyrene-treated A/J mice and K-rasLAC57Bl6/129/sv F1 mice with no detectable toxicity. Our findings support the potential use of deguelin in a liposomal formulation via lung-specific delivery to improve efficacy and to reduce the potential side effects of the agent.chemDEGUELINdiseaseLUNG NEOPLASMSgeneAKT1geneNOS3geneCASP3geneCDK4geneEPAS1geneMAP2K2geneGSK3BgeneMAP2K1action termexpressionaction termphosphorylationaction termactivityixndeguelin has a real or putative therapeutic role towards Lung Neoplasmsixndeguelin results in increased activity of CASP3 proteinixndeguelin results in decreased expression of AKT1 proteinixndeguelin results in decreased phosphorylation of AKT1 proteinixndeguelin results in decreased phosphorylation of GSK3B proteinixndeguelin results in decreased expression of CDK4 proteinixndeguelin results in decreased expression of MAP2K1 proteinixndeguelin results in decreased expression of MAP2K2 proteinixndeguelin results in decreased expression of EPAS1 proteinixndeguelin results in decreased expression of NOS3 protein19595700title0Bromocriptine induces parapoptosis as the main type of cell death responsible for experimental pituitary tumor shrinkage.abstract122Bromocriptine (Bc) produces pituitary tumoral mass regression which induces the cellular death that was classically described as apoptosis. However, recent works have related that other mechanisms of cell death could also be involved in the maintenance of physiological and pathological pituitary homeostasis. The aim of this study was to evaluate and characterize the different types of cell death in the involution induced by Bc in experimental rat pituitary tumors. The current study demonstrated that Bc induced an effective regression of estrogen induced pituitary tumors by a mechanism identified as parapoptosis. This alternative cell death was ultrastructurally recognized by extensive cytoplasmic vacuolization and an increased cell electron density, represented around 25% of the total pituitary cells counted. Furthermore, the results obtained from biochemical assays did not correspond to the criteria of apoptosis or necrosis. We also investigated the participation of p38, ERK1/2 and PKC delta in the parapoptotic pathway. An important observation was the significant increase in phosphorylated forms of these MAPKs, the holoenzyme and catalytic fragments of PKC delta in nuclear fractions after Bc administration compared to control and estrogen treated rats. Furthermore, the immunolocalization at ultrastructural level of these kinases showed a similar distribution pattern, with a prevalent localization at nuclear level in lactotrophs from Bc treated rats. In summary, we determined that parapoptosis is the predominant cell death type involved in the regression of pituitary tumors in response to Bc treatment, and may cause the activation of PKC delta, ERK1/2 and p38.chemESTROGENSchemBROMOCRIPTINEdiseasePITUITARY NEOPLASMSgenePRKCDgeneMAPK3geneMAPK1action termreactionaction termexpressionaction termlocalizationaction termphosphorylationaction termcleavageixnBromocriptine affects the localization of PRKCD proteinixnEstrogens plays a role in or acts as a marker for Pituitary NeoplasmsixnBromocriptine has a real or putative therapeutic role towards Pituitary NeoplasmsixnEstrogens results in increased expression of and results in increased cleavage of PRKCD proteinixnBromocriptine promotes the reaction [Estrogens results in increased expression of and results in increased cleavage of PRKCD protein]ixnEstrogens results in increased phosphorylation of and affects the localization of MAPK1 proteinixnEstrogens results in increased phosphorylation of and affects the localization of MAPK3 proteinixnBromocriptine promotes the reaction [Estrogens results in increased phosphorylation of and affects the localization of MAPK3 protein]ixnBromocriptine promotes the reaction [Estrogens results in increased phosphorylation of and affects the localization of MAPK1 protein]18511912title0Regulation of myosin light chain kinase expression by angiotensin II in hypertension.abstract86BACKGROUND: Increased growth and contraction of vascular smooth muscle cells (VSMCs) are major abnormalities in many vascular disorders. To investigate the signaling pathways that mediate these processes, we studied the expression of smooth muscle myosin light chain kinase (smMLCK) in VSMCs.
METHODS: Primary cultured VSMCs isolated from normotensive Wistar-Kyoto (WKY) rats were treated with angiotensin II (Ang II). smMLCK expression was examined in the cells using western blot analysis. In vivo, a specific inhibitor of smMLCK or MAP kinase kinase (MEK) was delivered to spontaneously hypertensive rats (SHRs) using an osmotic pump, and their blood pressures were measured using tail-cuff sphygmomanometry.
RESULTS: Expression of smMLCK protein is rapidly increased by Ang II, an important agonist responsible for increased vasoconstriction and vascular remodeling, in concert with increased myosin light chain phosphorylation. Inhibiting Ang II type 1 (AT1) receptor, Ras, or MEK blocked the Ang II-induced increase in smMLCK expression. In vivo, inhibiting MEK decreased smMLCK expression, blood pressure, and vascular thickening in SHRs. Moreover, inhibiting smMLCK activity decreased blood pressure and smooth muscle mass in arteries in SHRs.
CONCLUSIONS: The regulation of smMLCK expression by Ang II via Ras signaling is important in the regulation of vascular remodeling and blood pressure. Targeting this pathway could be an effective strategy for developing novel therapeutics to treat hypertension.chemU 0126chemLOSARTANdiseaseVASCULAR DISEASESgeneMYLKgeneMAPK3geneMAPK1geneMYL9geneAGTaction termexpressionaction termreactionaction termphosphorylationixnLosartan inhibits the reaction [AGT protein results in increased expression of MYLK protein]ixnLosartan inhibits the reaction [AGT protein results in increased phosphorylation of MAPK1 protein]ixnLosartan inhibits the reaction [AGT protein results in increased phosphorylation of MAPK3 protein]ixnU 0126 inhibits the reaction [AGT protein results in increased phosphorylation of MAPK3 protein]ixnMYLK plays a role in or acts as a marker for Vascular DiseasesixnU 0126 inhibits the reaction [AGT protein results in increased expression of MYLK protein]ixnU 0126 inhibits the reaction [AGT protein results in increased phosphorylation of MAPK1 protein]ixnU 0126 inhibits the reaction [AGT protein results in increased phosphorylation of MYL9 protein]ixnMYL9 plays a role in or acts as a marker for Vascular Diseases19391036title0Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms and therapy-related toxicity in children treated for acute lymphoblastic leukemia and non-Hodgkin lymphoma.abstract180This study aimed to investigate the association of the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms with serum drug levels and toxicities after high-dose methotrexate (MTX) infusion. The study included 37 children with acute lymphoblastic leukemia or non-Hodgkin lymphoma. Serum MTX levels and toxicities of bone marrow, liver and kidney were analysed. Genotype analysis of the C677T and A1298C gene polymorphisms from genomic DNA of the subjects was performed by real-time PCR. Subjects with MTHFR polymorphism for C677T (CT, TT) had significantly higher MTX levels at 24 h (p = 0.009), and these genotypes did not seem to cause toxicity. Subjects with MTHFR polymorphism for A1298C (AC, CC) had significantly higher MTX levels at 48 h (p = 0.02), and had more grade III/IV anemia (p = 0.02), thrombocytopenia (p = 0.0001), elevated AST levels (p = 0.04) and frequent febrile neutropenic episodes (p = 0.004). The present study suggests that A1298C gene, but not C677T polymorphism is associated with MTX-related toxicity.chemMETHOTREXATEdiseaseTHROMBOCYTOPENIAdiseaseDRUG TOXICITYdiseaseNEUTROPENIAdiseaseANEMIAgeneMTHFRaction termmetabolic processingixnMTHFR plays a role in or acts as a marker for NeutropeniaixnMTHFR plays a role in or acts as a marker for Drug ToxicityixnMethotrexate plays a role in or acts as a marker for Drug ToxicityixnMethotrexate plays a role in or acts as a marker for AnemiaixnMTHFR plays a role in or acts as a marker for AnemiaixnMTHFR protein results in increased metabolism of MethotrexateixnMTHFR plays a role in or acts as a marker for ThrombocytopeniaixnMethotrexate plays a role in or acts as a marker for ThrombocytopeniaixnMethotrexate plays a role in or acts as a marker for NeutropeniaixnMTHFR gene SNP results in decreased metabolism of Methotrexate21030459title0The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers.abstract123The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harboring a RANBP2-ALK translocation who progressed while on crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth, and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib-mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, and the HSP90 inhibitor 17-AAG are both effective in models harboring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers.chemNVP-TAE684chemTANESPIMYCINchemCRIZOTINIBdiseaseGRANULOMA, PLASMA CELLgeneRANBP2geneALKaction termreactionaction termmutagenesisaction termactivityaction termresponse to substanceixntanespimycin results in decreased activity of ALK protein mutant formixnNVP-TAE684 results in decreased activity of ALK protein mutant formixnRANBP2 plays a role in or acts as a marker for Granuloma, Plasma CellixnALK plays a role in or acts as a marker for Granuloma, Plasma Cellixncrizotinib results in increased mutagenesis of ALK protein mutant formixn[crizotinib results in increased mutagenesis of ALK protein mutant form] which results in increased activity of ALK proteinixn[crizotinib results in increased mutagenesis of ALK protein mutant form] which results in decreased susceptibility to crizotinibixncrizotinib results in decreased activity of ALK proteinixnALK protein mutant form inhibits the reaction [crizotinib results in decreased activity of ALK protein]7906944title0Glutamate-dopamine interactions in the production of pilocarpine motor seizures in the mouse.abstract94An assortment of glutamate antagonists with differing selectivities for NMDA and AMPA-type glutamate receptors, were tested for their effects in the mouse pilocarpine model of complex partial seizures. MK 801 (0.1-0.8 mg/kg) and high doses of HA 966 (50 mg/kg) were proconvulsant, whilst CGP 40116 (1-8 mg/kg) and low doses of HA 966 (0.4-10 mg/kg) inhibited pilocarpine-induced convulsions. CPP (5-20 mg/kg) and NBQX (1-50 mg/kg) were without effect. The dopamine D1 agonist SKF 38393 (10 mg/kg) facilitated the convulsant effects of low-dose pilocarpine (100 mg/kg). MK 801 (0.1-0.2 mg/kg) and HA 966 (50 mg/kg) interacted synergistically with SKF 38393 to promote the proconvulsant effects of D1 stimulation, whilst CPP (10-20 mg/kg) and HA 966 (10 mg/kg) had the opposite effect. CGP 40116 and NBQX were without effect. These results show that the convulsant qualities of MK 801 and SKF 38393, that have been detected in animal models of Parkinson''s disease, can be reproduced in the pilocarpine model of epilepsy. Whilst the glutamate antagonists all interact synergistically with SKF 38393 to improve its antiparkinson activity, only MK 801 and high doses of HA 966 similarly potentiate the convulsions associated with D1 stimulation. An appropriate mixture of a glutamate antagonist and a D1 agonist could theoretically be used beneficially in the treatment of Parkinson''s disease, without causing epilepsy as a side effect.chemPILOCARPINEchemDIZOCILPINE MALEATEchemEXCITATORY AMINO ACID ANTAGONISTSchem2,3,4,5-TETRAHYDRO-7,8-DIHYDROXY-1-PHENYL-1H-3-BENZAZEPINEchemHA 966diseaseSEIZURESgeneDRD1Aaction termbindingaction termcotreatmentaction termactivityaction termresponse to substanceixnPilocarpine plays a role in or acts as a marker for Seizuresixn[[2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine co-treated with Dizocilpine Maleate] co-treated with [HA 966 results in increased activity of DRD1A protein]] results in increased susceptibility to PilocarpineixnDizocilpine Maleate plays a role in or acts as a marker for SeizuresixnExcitatory Amino Acid Antagonists has a real or putative therapeutic role towards Seizuresixn2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine plays a role in or acts as a marker for SeizuresixnHA 966 plays a role in or acts as a marker for SeizuresixnHA 966 has a real or putative therapeutic role towards Seizuresixn2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine binds to and results in increased activity of DRD1A proteinixn[2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine binds to and results in increased activity of DRD1A protein] which results in increased susceptibility to Pilocarpine19293598title0Reduction in VEGF protein and phosphorylated nephrin associated with proteinuria in adriamycin nephropathy rats.abstract113BACKGROUND/AIMS: The relationship between vascular endothelial growth factor (VEGF) and the phosphorylated critical podocyte slit diaphragm molecule nephrin is not fully clarified. This study investigated the dynamic changes in VEGF expression and nephrin phosphorylation, and the effects of the antiproteinuric drugs prednisone and lisinopril on them in Adriamycin nephropathy rats.
METHODS: Renal tissues from Adriamycin rats were collected at days 3, 7, 14, and 28. Distribution and expression of VEGF was revealed by immunohistochemistry, real-time PCR and Western blot. Phosphorylated nephrin was evaluated by immunoprecipitation.
RESULTS: A discontinuous redistribution of VEGF was displayed at day 3, followed by significant protein reduction at day 7 with persistent downregulation to day 28. Phosphorylated nephrin decreased evidently at day 14 and persisted to day 28. The reduction in VEGF and phosphorylated nephrin was not a result of podocyte loss. The intervention of prednisone and lisinopril evidently reduced proteinuria, effectively attenuated the severe lesions of podocyte foot processes, and restored the reduction in VEGF and nephrin phosphorylation. At day 28, the reduction in VEGF and phosphorylated nephrin was negatively correlated with proteinuria, whereas the phosphorylated nephrin was positively correlated with VEGF protein from day 7 to day 28.
CONCLUSION: The reduction in VEGF protein and nephrin phosphorylation was possibly involved in the proteinuria in Adriamycin rats, and there might be some relationship between VEGF and nephrin phosphorylation. The antiproteinuric effects of lisinopril and prednisone were achieved at least partially by restoring VEGF protein and nephrin phosphorylation.chemLISINOPRILchemPREDNISONEchemDOXORUBICINdiseasePROTEINURIAgeneNPHS1geneVEGFAaction termreactionaction termexpressionaction termphosphorylationixnDoxorubicin results in decreased phosphorylation of NPHS1 proteinixnDoxorubicin plays a role in or acts as a marker for ProteinuriaixnPrednisone has a real or putative therapeutic role towards ProteinuriaixnLisinopril has a real or putative therapeutic role towards ProteinuriaixnPrednisone affects the reaction [Doxorubicin results in decreased expression of VEGFA protein]ixnDoxorubicin results in decreased expression of VEGFA proteinixnPrednisone inhibits the reaction [Doxorubicin results in decreased phosphorylation of NPHS1 protein]ixnLisinopril inhibits the reaction [Doxorubicin results in decreased expression of VEGFA protein]ixnLisinopril inhibits the reaction [Doxorubicin results in decreased phosphorylation of NPHS1 protein]17923031title0[The role of secreted Wnt-antagonist genes hypermethylation in early detection of colorectal tumor].abstract101OBJECTIVE: To investigate the functions of promoter hypermethylation of secreted Wnt-antagonist genes in colorectal tumorigenesis and progression.
METHODS: Two colorectal cancer cell lines, HCT116 and SW480, were treated by 5-aza-2''-deoxycytidine (DAC) and trichostatin A (TSA) for demethylation. The promoter hypermethylation and expression of sFRP and WIF-1 genes in different stages of colorectal tumor and colorectal cancer cell lines were detected by methylation-specific PCR and reverse transcription PCR, respectively.
RESULTS: None of the normal colorectal mucosa samples showed methylated bands of any sFRP and WIF-1genes. Hypermethylation of sFRP1, 2, 4, 5 and WIF-1 was detected in 93.1% (67/72), 83.3% (60/72), 36.1% (26/72), 52.8% (38/72) and 84.7% (61/72) of adenocarcinomas, 87.9% (29/33), 81.8% (27/33), 24.2% (8/33), 57.6% (19/33) and 72.7% (24/33) of adenomas, 52.6%, 28.9%, 2.6%, 18.4%, 23.7% of the adjacent normal mucosa. Methylation was more frequently found in colorectal tumors than in normal mucosa and adjacent normal mucosa from patients with tumor (P < 0.05). No significant association between Wnt-antagonist genes hypermethylation and clinicopathological characteristics was found (P > 0.05). SFRP1, 2, 4, 5 and WIF-1 genes were methylated in HCT116 cell line. SFRP1, 2 and WIF-1 were methylated in SW480 cell line. The mRNA expression of sFRPs and WIF-1 genes was absent or significantly downregulated (P < 0.01) when they were methylated in two colorectal cancer cell lines. SFRP3 was expressed in two colorectal carcinoma cell lines. DAC/TSA combination treatment re-expressed the silenced sFRPs and WIF-1 genes mRNA expressions effectively. A single application of TSA could not re-express sFRPs and WIF-1 genes mRNA expressions. The influence of demethylation treatment on sFRP3 expression was minimal.
CONCLUSION: Hypermethylation of Wnt-antagonist genes is a common early event in the evolution of colorectal tumor. Methylation of sFRP1, 2, 5 and WIF-1 genes might serve as biomarkers for the early detection of colorectal tumor.chemDECITABINEchemTRICHOSTATIN AdiseaseCOLORECTAL NEOPLASMSgeneSFRP5geneSFRP1geneSFRP2geneSFRP4geneWIF1action termexpressionaction termcotreatmentixnSFRP1 plays a role in or acts as a marker for Colorectal NeoplasmsixnSFRP2 plays a role in or acts as a marker for Colorectal NeoplasmsixnSFRP4 plays a role in or acts as a marker for Colorectal NeoplasmsixnSFRP5 plays a role in or acts as a marker for Colorectal NeoplasmsixnWIF1 plays a role in or acts as a marker for Colorectal Neoplasmsixn[decitabine co-treated with trichostatin A] results in increased expression of SFRP4 mRNAixn[decitabine co-treated with trichostatin A] results in increased expression of SFRP1 mRNAixn[decitabine co-treated with trichostatin A] results in increased expression of SFRP2 mRNAixn[decitabine co-treated with trichostatin A] results in increased expression of SFRP5 mRNAixn[decitabine co-treated with trichostatin A] results in increased expression of WIF1 mRNA19692487title0Mice lacking mPGES-1 are resistant to lithium-induced polyuria.abstract64Cyclooxygenase-2 activity is required for the development of lithium-induced polyuria. However, the involvement of a specific, terminal prostaglandin (PG) isomerase has not been evaluated. The present study was undertaken to assess lithium-induced polyuria in mice deficient in microsomal prostaglandin E synthase-1 (mPGES-1). A 2-wk administration of LiCl (4 mmol.kg(-1).day(-1) ip) in mPGES-1 +/+ mice led to a marked polyuria with hyposmotic urine. This was associated with elevated renal mPGES-1 protein expression and increased urine PGE(2) excretion. In contrast, mPGES-1 -/- mice were largely resistant to lithium-induced polyuria and a urine concentrating defect, accompanied by nearly complete blockade of high urine PGE(2) and cAMP output. Immunoblotting, immunohistochemistry, and quantitative (q) RT-PCR consistently detected a significant decrease in aquaporin-2 (AQP2) protein expression in both the renal cortex and medulla of lithium-treated +/+ mice. This decrease was significantly attenuated in the -/- mice. qRT-PCR detected similar patterns of changes in AQP2 mRNA in the medulla but not in the cortex. Similarly, the total protein abundance of the Na-K-2Cl cotransporter (NKCC2) in the medulla but not in the cortex of the +/+ mice was significantly reduced by lithium treatment. In contrast, the dowregulation of renal medullary NKCC2 expression was significantly attenuated in the -/- mice. We conclude that mPGES-1-derived PGE(2) mediates lithium-induced polyuria likely via inhibition of AQP2 and NKCC2 expression.chemLITHIUM CHLORIDEchemDINOPROSTONEdiseasePOLYURIAgenePTGESgeneSLC12A1geneAQP2action termreactionaction termexpressionaction termchemical synthesisixn[Lithium Chloride results in increased expression of PTGES protein] which results in increased chemical synthesis of DinoprostoneixnLithium Chloride plays a role in or acts as a marker for PolyuriaixnPTGES plays a role in or acts as a marker for PolyuriaixnLithium Chloride results in increased expression of PTGES proteinixnLithium Chloride results in decreased expression of AQP2 proteinixnLithium Chloride results in decreased expression of AQP2 mRNAixnLithium Chloride results in decreased expression of SLC12A1 proteinixnPTGES protein promotes the reaction [Lithium Chloride results in decreased expression of AQP2 protein]ixnPTGES protein promotes the reaction [Lithium Chloride results in decreased expression of SLC12A1 protein]ixnPTGES protein promotes the reaction [Lithium Chloride results in decreased expression of AQP2 mRNA]17944888title0Disruption of tissue-type plasminogen activator gene in mice aggravated liver fibrosis.abstract88BACKGROUND AND AIM: Tissue-type plasminogen activator (tPA) is one of the major components in the matrix proteolytic network whose role in the pathogenesis of liver fibrosis remains unknown. The aim of this study is to investigate the role of tPA in carbon tetrachloride (CCl(4))-induced liver fibrosis.
METHODS: Wild-type and tPA knockout mice (8 mice per group) were injected interperitoneumly with 25% CCl(4) 2 ml/kg twice per week as CCl(4) administration groups and olive oil 2 ml/kg as controls. After 4 weeks, the livers of mice were removed under deep anesthesia and prepared for further studies such as histology, immunostaining, hydroxyproline assay, zymography and western blot analysis.
RESULTS: Mice lacking tPA developed more severe morphological injury and displayed an increased deposition of collagen in the liver after CCl(4) administration compared with wild-type counterparts. Deficiency of tPA increased alpha-smooth muscle actin expression in the mice livers. On the other hand, the decrease of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) activities, metalloproteinase-13 (MMP-13) expression and a marked increase of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) expression were found in the liver of CCl(4) administrated tPA(-/-) mice compared with wild-type counterparts.
CONCLUSIONS: Deficiency of tPA aggravated liver fibrosis through promoting hepatic stellate cells (HSCs) activation and inhibiting ECM degradation by decreasing MMP-2, MMP-9 activities and disrupting the balance between MMP-13 and TIMP-1.chemCARBON TETRACHLORIDEdiseaseLIVER CIRRHOSIS, EXPERIMENTALgeneTIMP1geneMMP9geneMMP13geneMMP2genePLATaction termreactionaction termexpressionixnCarbon Tetrachloride plays a role in or acts as a marker for Liver Cirrhosis, ExperimentalixnCarbon Tetrachloride results in increased expression of MMP2 proteinixnPLAT protein affects the reaction [Carbon Tetrachloride results in increased expression of MMP2 protein]ixnCarbon Tetrachloride results in increased expression of MMP9 proteinixnPLAT protein affects the reaction [Carbon Tetrachloride results in increased expression of MMP9 protein]ixnCarbon Tetrachloride results in increased expression of MMP13 proteinixnPLAT protein affects the reaction [Carbon Tetrachloride results in increased expression of MMP13 protein]ixnCarbon Tetrachloride results in increased expression of TIMP1 proteinixnPLAT protein affects the reaction [Carbon Tetrachloride results in increased expression of TIMP1 protein]20934418title0Gastroprotective mechanisms of Citrus lemon (Rutaceae) essential oil and its majority compounds limonene and -pinene: involvement of heat-shock protein-70, vasoactive intestinal peptide, glutathione, sulfhydryl compounds, nitric oxide and prostaglandin E .abstract258Citrus lemon (CL) belongs to Rutaceae family and is popularly known in Brazil as lim o siciliano. The phytochemical analysis of CL fruit bark essential oil showed two majority components, limonene (LIM) and -pinene (PIN). This study aimed to evaluate the gastroprotective mechanism of action from CL, LIM and PIN in ethanol- and indomethacin-induced gastric ulcers and its in vitro anti-Helicobacter pylori activity. After ethanol-induced gastric ulcer, the ulcer area was measured and the stomachs were destined to histology (HE and PAS), immunohistochemistry for HSP-70 and VIP and glutathione (GSH) measurement. The involvement of nitric oxide (NO) and sulfhydryl (SH) compounds was determined. The ulcer area for indomethacin-induced gastric ulcers was measured. PGE concentration was biochemically measured. The minimum inhibitory concentration (MIC) against H. pylori was determined in vitro. In ethanol model, CL and LIM demonstrated 100% of gastroprotection, while PIN did not exert effective gastroprotection (53.26%). In the indomethacin model, CL and LIM offered effective gastroprotection but PIN did not show gastroprotective effect. The gastric ulcer area of rats pretreated with NO-synthase inhibitor or SH-blocker was decreased in comparison to the control group. The MIC obtained for CL was 125 g/mL, for LIM was 75 g/mL and for PIN was 500 g/mL. The gastroprotective effect of CL and LIM was involved with increasing in mucus secretion, HSP-70 and VIP, but not with GSH, NO or SH compounds. CL gastroprotective mechanism is involved with PGE . PIN did not present gastroprotective activity.chemLEMON OILchemETHANOLchemCIMETIDINEchemBETA-PINENEchemINDOMETHACINchemCARBENOXOLONEchemLIMONENEdiseaseSTOMACH ULCERgeneVIPaction termexpressionixnEthanol plays a role in or acts as a marker for Stomach Ulcerixnlemon oil has a real or putative therapeutic role towards Stomach UlcerixnIndomethacin plays a role in or acts as a marker for Stomach Ulcerixnlimonene has a real or putative therapeutic role towards Stomach Ulcerixnlemon oil results in increased expression of VIP proteinixnbeta-pinene results in increased expression of VIP proteinixnCimetidine has a real or putative therapeutic role towards Stomach Ulcerixnlimonene results in increased expression of VIP proteinixnCarbenoxolone has a real or putative therapeutic role towards Stomach Ulcer19327236title0Effects of celecoxib on the expression of osteoprotegerin, energy metabolism and cell viability in cultured human osteoblastic cells.abstract134BACKGROUND AND OBJECTIVE: The selective COX-2 inhibitor celecoxib is widely used to treat pain and inflammation in rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. The drug has well-known important effects on immune cells but its direct and/or indirect influence on osteoblasts has not yet been explored in detail. This study aimed to investigate the dose-dependent effects of celecoxib on cell viability, energy metabolism and bone remodeling processes in cultured human osteoblastic cells.
METHODS: Primary human osteoblasts and MG-63 cells were incubated with celecoxib (2, 10, 50microM). Cell viability and apoptosis were determined by trypan blue, 7AAD and Annexin-V staining. Effects on cellular oxygen consumption were measured amperometrically using a Clark electrode. mRNA expression of GLUT-1 and OPG was determined by RT-PCR; OPG protein secretion by ELISA and HIF-1alpha protein expression by immunoblotting.
RESULTS: While celecoxib at a concentration of 2 and 10microM showed only marginal effects, a suprapharmacological concentration of 50microM influenced viability and energy metabolism, as well as OPG expression and secretion of osteoblastic cells. Cell viability was significantly reduced by celecoxib treatment. Celecoxib at 50microM stimulated oxygen consumption significantly. Corresponding experiments with the protonophore FCCP suggest that this effect is due to mitochondrial uncoupling. After 24h, GLUT-1 mRNA expression was significantly increased. HIF-1alpha protein was not expressed under any of our experimental conditions. We also showed that celecoxib at 50microM significantly inhibits OPG protein secretion leading to a compensative increase of mRNA expression.
CONCLUSION: Pronounced effects of celecoxib on cell viability (reduction), oxygen consumption (stimulation), GLUT-1 mRNA expression (stimulation) and OPG protein secretion (inhibition) in osteoblastic cells were observed only at 50microM-a concentration not reached by therapeutic doses giving plasma concentrations less than 10microM. On the contrary, celecoxib at 2 and 10microM showed only marginal effects, suggesting that celecoxib administration is probably safe with respect to bone metabolism in cases requiring potent treatment of pain and inflammation. However, higher intracellular concentrations, which might occur through accumulation, necessitate investigations with high concentrations.chemCELECOXIBdiseaseINFLAMMATIONdiseasePAINgenePTGS2geneTNFRSF11BgeneSLC2A1action termexpressionaction termsecretionaction termactivityixncelecoxib has a real or putative therapeutic role towards Inflammationixncelecoxib results in increased expression of TNFRSF11B mRNAixncelecoxib has a real or putative therapeutic role towards Painixncelecoxib results in decreased secretion of TNFRSF11B proteinixncelecoxib results in decreased activity of PTGS2 proteinixncelecoxib results in increased expression of SLC2A1 mRNA6760236title0Long-term effects of 1,25-dihydroxy vitamin D3 and 24,25-dihydroxy vitamin D3 in renal osteodystrophy.abstract103Twenty-three patients with end-stage renal failure on maintenance haemodialysis were treated with 1,25-dihydroxy vitamin D3 or 24-25-dihydroxy vitamin D3 for 3-32 months (total 232 patient months). Treatment with 1,25-dihydroxy vitamin D3 was marked by symptomatic, biochemical and histological improvements in the majority of patients. In contrast, treatment with 24,25-dihydroxy vitamin D3 produced no biochemical or histological improvements and such patients developed severe symptomatic bone disease. Successful renal transplantation resulted in rapid improvement in symptoms, biochemistry and bone histology in nine of 10 patients irrespective of whether prior treatment was with 1,25-dihydroxy vitamin D3, 24,25-dihydroxy vitamin D3 or both. During treatment with 1,25-dihydroxy vitamin D3 progressive reduction in dosage was required in the majority of patients because of hypercalcaemia, which was rapidly corrected by stopping treatment for a few days. Hypercalcaemia did not occur until serum alkaline phosphatase (AP) and amino terminal parathyroid hormone (N-PTH) had fallen towards normal. Treatment failure was uncommon in 1,25-dihydroxy vitamin D3-treated patients and was characterized by the early development of hypercalcaemia. Addition of 24,25-dihydroxy vitamin D3 in such patients rendered the hypercalcaemia more manageable but did not lead to any further improvement in biochemistry or bone histology. Treatment with 24,25-dihydroxy vitamin D3 was accompanied by the development of severe symptomatic bone disease in the majority of patients and a characteristic pattern of biochemical abnormalities with hypocalcaemia and rises in AP and N-PTH. Substitution of 1,25-dihydroxy vitamin D3 treatment for 24,25-dihydroxy vitamin D3 in these patients resulted in prompt improvement in clinical, biochemical and histological abnormalities. Successful renal transplantation was accompanied by rapid resolution of clinical, biochemical and histological features of renal osteodystrophy irrespective of whether previous treatment was with 1,25-dihydroxy vitamin D3 or 24,25-dihydroxy vitamin D3. Hypophosphataemia was common in the early months after renal transplantation without evidence of continuing hyperparathyroidism. The studies have confirmed that 1,25-dihydroxy vitamin D3 is effective in controlling clinical, biochemical and histological features of renal osteodystrophy while 24,25-dihydroxy vitamin D3 did not have a useful therapeutic effect in the dose used.chemCALCITRIOLchem24,25-DIHYDROXYVITAMIN D 3diseaseHYPOCALCEMIAdiseaseBONE DISEASES, METABOLICdiseaseHYPERCALCEMIAdiseaseRENAL OSTEODYSTROPHYdiseaseKIDNEY FAILURE, CHRONICgenePTHaction termexpressionixnCalcitriol has a real or putative therapeutic role towards Kidney Failure, ChronicixnCalcitriol plays a role in or acts as a marker for Hypercalcemiaixn24,25-Dihydroxyvitamin D 3 plays a role in or acts as a marker for Bone Diseases, Metabolicixn24,25-Dihydroxyvitamin D 3 has a real or putative therapeutic role towards HypercalcemiaixnCalcitriol results in decreased expression of PTH proteinixn24,25-Dihydroxyvitamin D 3 plays a role in or acts as a marker for Hypocalcemiaixn24,25-Dihydroxyvitamin D 3 results in increased expression of PTH proteinixnCalcitriol plays a role in or acts as a marker for HypocalcemiaixnCalcitriol has a real or putative therapeutic role towards Renal Osteodystrophy11375891title0Rat colorectal tumours treated with a range of non-steroidal anti-inflammatory drugs show altered cyclooxygenase-2 and cyclooxygenase-1 splice variant mRNA expression levels.abstract175Non-steroidal anti-inflammatory drugs (NSAIDs) reduce tumour mass by increasing the rate of tumour cell apoptosis and decreasing cell proliferation. The classically recognized target for NSAID action are the two isoforms of the cyclooxygenase (COX) gene, which is responsible for prostaglandin production. In the rat, the COX-1 gene expresses an alternatively spliced mRNA COX-1 splice variant (SV) which may, at best, code for a truncated COX-1 protein. Previously, we reported that COX-1SV mRNA is differentially expressed in the ageing stomach. In this study, carcinogen treated rats were treated for 23 weeks with celecoxib, sulindac or sulindac sulfone, while untreated rats received vehicle alone. For each animal, the number and volume of tumour per animal was recorded and histology was performed. Using competitive polymerase chain reaction, we determined whether COX gene expression was altered in colorectal tumours and in regions of adjacent and distant macroscopically normal intestine, from vehicle or NSAID treated rats. In addition, we immunolocalized COX-1 and COX-2 in the same tumour and normal colonic tissue. Tumours from animals treated with vehicle or celecoxib expressed significantly elevated levels of COX-2 mRNA in comparison with the adjacent normal mucosa. In contrast, tumours from sulindac and sulindac sulfone treated rats expressed significantly less COX-2 mRNA than tumours from vehicle treated rats. The expression of COX-1 mRNA remained unchanged in all tissues examined. However, COX-1SV mRNA levels were elevated in colorectal tumours and reduced after NSAID treatment to the levels observed in normal colonic mucosa. Our results indicate that the anti-neoplastic actions of NSAIDs may be attributed to COX dependent and/or COX independent mechanisms of action. We also demonstrate the presence and differential expression of COX-1SV mRNA in colon tumours. COX-1SV mRNA represents 2% of the total COX-1 mRNA expressed and its role in colon cancer remains to be established.chemSULINDAC SULFONEchemSULINDACchemCELECOXIBdiseaseCOLORECTAL NEOPLASMSgenePTGS2genePTGS1action termexpressionixnPTGS2 plays a role in or acts as a marker for Colorectal NeoplasmsixnSulindac results in decreased expression of PTGS2 mRNAixnsulindac sulfone results in decreased expression of PTGS2 mRNAixncelecoxib does not affect the expression of PTGS2 mRNAixnSulindac does not affect the expression of PTGS1 mRNAixnsulindac sulfone does not affect the expression of PTGS1 mRNAixncelecoxib does not affect the expression of PTGS1 mRNAixnSulindac results in decreased expression of PTGS1 mRNA alternative formixnsulindac sulfone results in decreased expression of PTGS1 mRNA alternative formixncelecoxib results in decreased expression of PTGS1 mRNA alternative form17515069title0Adverse events of MVAC chemotherapy in patients with advanced urothelial cancer of the bladder.abstract96There have only been a few reports about adverse events of methotrexate, vinblastine, adriamycin and cisplatin (MVAC) chemotherapy under supportive care with granulocyte stimulating factor (G-CSF) and 5-hydroxytryptamine 3 receptor (5-HT3R) antagonists. The purpose of this study was to retrospectively review the adverse events of the chemotherapy. We analyzed 59 patients with advanced bladder cancer who received MVAC chemotherapy at Sapporo Medical University hospital from January 1992 to September 2004. The adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 3.0 (Japanese edition). Thirty-one of the 59 patients (52.6%) received MVAC in the neoadjuvant setting. Two courses of chemotherapy were most frequently used in the neoadjuvant and adjuvant settings, and treatment of metastatic or recurrent lesions. More than 90% of patients experienced hematological adverse events such as some grade of leukocytopenia and neutropenia in each course of the chemotherapy. Grade 3 or 4 neutropenia was seen in 60-75% of patients. Grade 3 or 4 leukopenia and/or neutropenia in the first course of the chemotherapy was associated with patients with impaired renal function (60 mL/min< or = creatinine clearance <80 mL/min). Febrile neutropenia was found in 6 patients (5.0%), including one who died of subsequent septic shock and adult respiratory distress syndrome. Nausea was seen in 70-80% of patients. MVAC chemotherapy for advanced bladder cancer was performed with tolerable adverse events. The current results provide relevant information mainly for those who need 2 courses of chemotherapy in the neoadjuvant or adjuvant setting.chemM-VAC PROTOCOLchemSEROTONIN 5-HT3 RECEPTOR ANTAGONISTSdiseaseRENAL INSUFFICIENCYdiseaseSHOCK, SEPTICdiseaseLEUKOPENIAdiseaseRESPIRATORY DISTRESS SYNDROME, ADULTdiseaseURINARY BLADDER NEOPLASMSdiseaseNEUTROPENIAdiseaseNAUSEAgeneCSF3ixnM-VAC protocol plays a role in or acts as a marker for NauseaixnM-VAC protocol plays a role in or acts as a marker for Renal InsufficiencyixnM-VAC protocol has a real or putative therapeutic role towards Urinary Bladder NeoplasmsixnM-VAC protocol plays a role in or acts as a marker for Shock, SepticixnM-VAC protocol plays a role in or acts as a marker for LeukopeniaixnM-VAC protocol plays a role in or acts as a marker for NeutropeniaixnSerotonin 5-HT3 Receptor Antagonists has a real or putative therapeutic role towards Urinary Bladder NeoplasmsixnM-VAC protocol plays a role in or acts as a marker for Respiratory Distress Syndrome, AdultixnCSF3 has a real or putative therapeutic role towards Urinary Bladder Neoplasms20107430title0A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in Schizophrenia.abstract135Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with atypical antipsychotic drugs. The cannabinoid receptor 1 (CNR1) is expressed centrally in the hypothalamic region and associated with appetite and satiety, as well as peripherally. An antagonist of CNR1 (rimonabant) has been effective in causing weight loss in obese patients indicating that CNR1 might be important in antipsychotic-induced weight gain. Twenty tag SNPs were analyzed in 183 patients who underwent treatment (with either clozapine, olanzapine, haloperidol, or risperidone) for chronic schizophrenia were evaluated for antipsychotic-induced weight gain for up to 14 weeks. The polymorphism rs806378 was nominally associated with weight gain in patients of European ancestry treated with clozapine or olanzapine. ''T'' allele carriers (CT+TT) gained more weight (5.96%), than the CC carriers (2.76%, p=0.008, FDR q-value=0.12). This translated into approximately 2.2 kg more weight gain in patients carrying the T allele than the patients homozygous for the CC genotype (CC vs CT+TT, 2.21+/-4.51 vs 4.33+/-3.89 kg; p=0.022). This was reflected in the allelic analysis (C vs T allele, 3.84 vs 5.83%, p=0.035). We conducted electrophoretic mobility shift assays which showed that the presence of the T allele created a binding site for arylhydrocarbon receptor translocator (ARNT), a member of the basic helix-loop-helix/Per-Arnt-Sim protein family. In this study, we provide evidence that the CNR1 gene may be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. However, these observations were made in a relatively small patient population; therefore these results need to be replicated in larger sample sets.chemOLANZAPINEchemCLOZAPINEchemRIMONABANTchemHALOPERIDOLchemRISPERIDONEdiseaseWEIGHT GAINdiseaseSCHIZOPHRENIAdiseaseWEIGHT LOSSgeneCNR1action termbindingaction termactivityixnClozapine plays a role in or acts as a marker for Weight Gainixnolanzapine plays a role in or acts as a marker for Weight GainixnClozapine has a real or putative therapeutic role towards Schizophreniaixnolanzapine has a real or putative therapeutic role towards SchizophreniaixnRisperidone has a real or putative therapeutic role towards SchizophreniaixnHaloperidol has a real or putative therapeutic role towards SchizophreniaixnCNR1 plays a role in or acts as a marker for Weight Gainixnrimonabant plays a role in or acts as a marker for Weight Lossixnrimonabant binds to and results in decreased activity of CNR1 protein9794924title0Adenosine triphosphate-dependent transport of estradiol-17beta(beta-D-glucuronide) in membrane vesicles by MDR1 expressed in insect cells.abstract139MDR1, an ABC transporter that confers multidrug resistance in tumor cells, is constitutively expressed in normal liver canalicular membrane. Human MDR1-expressing multidrug-resistant cells display increased resistance to estradiol-17beta(beta-D-glucuronide) (E217G). MDR1 substrates/modulators inhibit adenosine triphosphate (ATP)-dependent transport of E217G in the rat canalicular membrane and protect against E217G-mediated cholestasis in isolated perfused rat liver. The present studies were designed to determine if E217G is a substrate for MDR1 using a baculovirus expression system and if other estrogen glucuronides interact with MDR1. ATP-dependent transport of E217G (10 micromol/L) was linear for up to 2 minutes and yielded a rate of 45.6 pmol/min/mg protein in membrane vesicles from Sf9 cells infected with MDR1-baculovirus. This transport was saturable (Km = 62 micromol/L) and occurred into an osmotically sensitive space. ATP-dependent transport of E217G (10 micromol/L) was inhibited 63% by 10 micromol/L daunomycin, but not by 100 micromol/L S-(2,4-dinitrophenyl)glutathione (GS-DNP) (a substrate for canalicular multispecific organic anion transporter [cMOAT]). Glucuronide conjugates of the estrogen D-ring (100 micromol/L), estriol-17beta(beta-D-glucuronide) (E317G) and estriol-16(beta-D-glucuronide) (E316G), inhibited MDR1-mediated E217G transport by 58% and 35%, respectively. In contrast, noncholestatic glucuronides, estradiol-3-(beta-D-glucuronide) (E23G) or estradiol-3-sulfate-17beta(beta-D-glucuronide) (E23SO417G), had no effect. E217G neither stimulated MDR1 ATPase activity nor inhibited verapamil-stimulated ATPase activity. Infusion of 1.5 micromol/L doxorubicin or 1 micromol/L taxol protected against cholestasis induced by E316G and E317G in isolated perfused rat liver. These studies identify E217G, and probably E316G and E317G, as endogenous substrates for MDR1.chemDOXORUBICINchemPACLITAXELchemESTRIOL 17-GLUCURONIDEchemESTRIOL-16 ALPHA-(BETA-D-GLUCURONIDE)chemDAUNORUBICINchemESTRADIOL-17 BETA-GLUCURONIDEdiseaseCHOLESTASISgeneABCB1action termreactionaction termtransportaction termresponse to substanceixnABCB1 results in increased transport of estradiol-17 beta-glucuronideixnDaunorubicin inhibits the reaction [ABCB1 results in increased transport of estradiol-17 beta-glucuronide]ixnestriol 17-glucuronide inhibits the reaction [ABCB1 results in increased transport of estradiol-17 beta-glucuronide]ixnestriol-16 alpha-(beta-D-glucuronide) inhibits the reaction [ABCB1 results in increased transport of estradiol-17 beta-glucuronide]ixnestriol-16 alpha-(beta-D-glucuronide) plays a role in or acts as a marker for Cholestasisixnestriol 17-glucuronide plays a role in or acts as a marker for CholestasisixnDoxorubicin has a real or putative therapeutic role towards CholestasisixnPaclitaxel has a real or putative therapeutic role towards CholestasisixnABCB1 affects the susceptibility to estradiol-17 beta-glucuronideixnestradiol-17 beta-glucuronide plays a role in or acts as a marker for Cholestasis12130717title0Morphine-3beta-D-glucuronide suppresses inhibitory synaptic transmission in rat substantia gelatinosa.abstract103High doses of intrathecally applied morphine or morphine-3beta-D-glucuronide (M3G) produce allodynia and hyperalgesia. Whole-cell patch-clamp recordings were made from substantia gelatinosa neurons in transverse slices of adult rat lumbar spinal cord to compare the actions of M3G with those of the mu-opioid agonist, DAMGO ([D-Ala(2),N-Met-Phe(4),Gly-ol(5)]-enkephalin), and the ORL(1) agonist, nociceptin/orphanin FQ (N/OFQ). M3G (1-100 microM) had little or no effect on evoked excitatory postsynaptic currents (EPSC) and no effect on postsynaptic membrane conductance. In contrast, 1 microM DAMGO and 1 microM N/OFQ reduced the amplitude of evoked EPSCs and activated an inwardly rectifying K(+) conductance. M3G did not attenuate the effect of DAMGO or N/OFQ on evoked EPSC amplitude. However, 1 to 100 microM M3G reduced the amplitude of evoked GABAergic and glycinergic inhibitory postsynaptic current (IPSC) by up to 48%. This effect was naloxone-insensitive. The evoked IPSC was also attenuated by DAMGO, but not by N/OFQ. Because M3G reduced the frequency of tetrodotoxin-insensitive miniature IPSCs and increased paired-pulse facilitation, it appeared to act presynaptically to disinhibit substantia gelatinosa neurons. This effect, which does not appear to involve mu-opioid or ORL(1) receptors, may contribute to the allodynia and hyperalgesia observed after intrathecal application of high doses of morphine.chemENKEPHALIN, ALA(2)-MEPHE(4)-GLY(5)-chemMORPHINE-3-GLUCURONIDEdiseaseHYPERALGESIAgenePNOCixnmorphine-3-glucuronide plays a role in or acts as a marker for Hyperalgesia18214922title0Ym1 and Ym2 expression in a mouse model exposed to diesel exhaust particles.abstract77BACKGROUND: Chitinase may play a role in regulating allergic diseases.
OBJECTIVE: We studied the role of chitinase in a mouse model exposed to diesel exhaust particles (DEP). Mice were exposed to intranasal DEP (0.6 mg/mL) for 5 days and challenged with aerosolized DEP (6 mg/m(3)) on days 6-8. Enhanced pause (Penh), as an airway obstruction marker, was measured on day 9, and bronchoalveolar lavage (BAL) fluid and lung tissues were collected on day 10. The expression of Ym1 and Ym2 mRNA was assessed in lung tissue extracts by reverse transcription-polymerase chain reaction.
RESULTS: DEP induced significant increases in methacholine-induced Penh and IL-4 levels in BAL fluid relative to the control group. Peribronchial and perivascular inflammatory cell infiltrates were prominent in the DEP group. DEP induced Ym1 and Ym2 mRNA expression in lung tissue extracts relative to the control group.
CONCLUSION: These results demonstrate that DEP induced airway hyperresponsiveness and Ym mRNA expression via a Th2 cell-biased response, suggesting that chitinase may play an important role in airway inflammation and responsiveness upon exposure to DEP in a mouse model, and may therefore be involved in regulating allergic diseases.chemMETHACHOLINE COMPOUNDSchemPARTICULATE MATTERchemVEHICLE EMISSIONSdiseaseBRONCHIAL HYPERREACTIVITYgeneCHI3L3geneCHI3L4geneIL4action termreactionaction termexpressionixnParticulate Matter results in increased expression of CHI3L3 mRNAixnParticulate Matter results in increased expression of CHI3L4 mRNAixnMethacholine Compounds results in increased expression of IL4 proteinixnParticulate Matter promotes the reaction [Methacholine Compounds results in increased expression of IL4 protein]ixnVehicle Emissions results in increased expression of CHI3L3 mRNAixnVehicle Emissions promotes the reaction [Methacholine Compounds results in increased expression of IL4 protein]ixnVehicle Emissions results in increased expression of CHI3L4 mRNAixnParticulate Matter plays a role in or acts as a marker for Bronchial HyperreactivityixnVehicle Emissions plays a role in or acts as a marker for Bronchial Hyperreactivity11274237title0Puromycin aminonucleoside suppresses integrin expression in cultured glomerular epithelial cells.abstract98Puromycin aminonucleoside (PAN)-induced nephrosis is a well-described model of human idiopathic nephrotic syndrome, but the mechanism of PAN''s effect is not completely understood. Because PAN injection into rats results in retraction of glomerular epithelial cell foot processes and glomerular epithelial cell detachment, it was hypothesized that PAN might alter the contacts between these cells and the glomerular basement membrane. The major integrin expressed by glomerular epithelial cells is alpha3beta1, which mediates attachment of these cells to extracellular matrix proteins including type IV collagen. T-SV 40 immortalized human glomerular epithelial cells were used to study PAN''s effects on alpha3beta1 expression, as well as that of podocalyxin and the slit diaphragm component ZO-1. Glomerular epithelial cells were seeded into plastic flasks and allowed to attach and proliferate for 48 h. The cells were then incubated for another 48 h in media containing 0, 0.5, or 5.0 microg/ml PAN. PAN exposure resulted in dose-dependent decreases in alpha3 and beta1 expression, both at the protein level and at the mRNA level. This was accompanied by a significant decrease in the adhesion of glomerular epithelial cells to type IV collagen. PAN did not affect ZO-1 protein expression. Treatment with PAN increased the expression of podocalyxin at the protein and mRNA levels. Reduced glomerular epithelial cell expression of alpha3beta1 integrins and impaired adhesion to type IV collagen may contribute to the glomerular epithelial cell detachment from glomerular basement membrane seen in the PAN nephrosis model.chemPUROMYCIN AMINONUCLEOSIDEdiseaseNEPHROSISdiseaseDISEASE MODELS, ANIMALdiseasePROTEINURIAgenePODXLgeneITGA3geneITGB1action termexpressionixnPuromycin Aminonucleoside plays a role in or acts as a marker for NephrosisixnPuromycin Aminonucleoside plays a role in or acts as a marker for Disease Models, AnimalixnPuromycin Aminonucleoside plays a role in or acts as a marker for ProteinuriaixnPuromycin Aminonucleoside results in decreased expression of ITGA3 proteinixnPuromycin Aminonucleoside results in decreased expression of ITGB1 proteinixnPuromycin Aminonucleoside results in decreased expression of ITGB1 mRNAixnPuromycin Aminonucleoside results in decreased expression of ITGA3 mRNAixnPuromycin Aminonucleoside results in increased expression of PODXL mRNAixnPuromycin Aminonucleoside results in increased expression of PODXL protein11390425title0T-cell involvement in drug-induced acute generalized exanthematous pustulosis.abstract79Acute generalized exanthematous pustulosis (AGEP) is an uncommon eruption most often provoked by drugs, by acute infections with enteroviruses, or by mercury. It is characterized by acute, extensive formation of nonfollicular sterile pustules on erythematous background, fever, and peripheral blood leukocytosis. We present clinical and immunological data on four patients with this disease, which is caused by different drugs. An involvement of T cells could be implied by positive skin patch tests and lymphocyte transformation tests. Immunohistochemistry revealed a massive cell infiltrate consisting of neutrophils in pustules and T cells in the dermis and epidermis. Expression of the potent neutrophil-attracting chemokine IL-8 was elevated in keratinocytes and infiltrating mononuclear cells. Drug-specific T cells were generated from the blood and skin of three patients, and phenotypic characterization showed a heterogeneous distribution of CD4/CD8 phenotype and of T-cell receptor Vbeta-expression. Analysis of cytokine/chemokine profiles revealed that IL-8 is produced significantly more by drug-specific T cells from patients with AGEP compared with drug-specific T cells from patients that had non-AGEP exanthemas. In conclusion, our data demonstrate the involvement of drug-specific T cells in the pathomechanism of this rather rare and peculiar form of drug allergy. In addition, they indicate that even in some neutrophil-rich inflammatory responses specific T cells are engaged and might orchestrate the immune reaction.chemCLARITHROMYCINchemAMOXICILLIN-POTASSIUM CLAVULANATE COMBINATIONchemCELECOXIBchemMERCURYchemAMOXICILLINdiseaseEXANTHEMAgeneIL8action termexpressionixnMercury plays a role in or acts as a marker for ExanthemaixnAmoxicillin-Potassium Clavulanate Combination plays a role in or acts as a marker for ExanthemaixnAmoxicillin plays a role in or acts as a marker for ExanthemaixnClarithromycin plays a role in or acts as a marker for Exanthemaixncelecoxib plays a role in or acts as a marker for ExanthemaixnAmoxicillin-Potassium Clavulanate Combination results in increased expression of IL8 proteinixnAmoxicillin results in increased expression of IL8 proteinixnClarithromycin results in increased expression of IL8 proteinixncelecoxib results in increased expression of IL8 protein16365282title0Loss of synaptic D1 dopamine/N-methyl-D-aspartate glutamate receptor complexes in L-DOPA-induced dyskinesia in the rat.abstract120Glutamate-mediated mechanisms are related to the motor complications of L-DOPA therapy in Parkinson''s disease (PD). In striatal postsynaptic densities (PSD), the dopamine D1 receptor (D1R) is part of an oligomeric complex with the glutamate N-methyl-D-aspartate receptor (NMDAR), determining the strength of corticostriatal transmission. We studied D1R/NMDAR complex alterations induced by L-DOPA in the 6-hydroxydopamine-lesioned rat model of PD. L-DOPA-treated hemiparkinsonian rats were determined to be dyskinetic or nondyskinetic based on behavioral testing. D1R/NMDAR assemblies containing NR1-C2 and NR2B subunits were decreased in the PSD of lesioned striatum. Short-term L-DOPA administration improved akinesia and restored the synaptic abundance of D1R, NR1-C2 and NR2B. Prolonged L-DOPA treatment also normalized synaptic D1R/NMDAR complexes in nondyskinetic rats, but remarkably reduced them in the dyskinetic group without changing their interaction. This decrease involved NR1-C2, NR1-C2'', NR2A, and NR2B subunits. The composition of residual synaptic D1R/NMDAR complexes in dyskinetic rats may thus be different from that observed in lesioned rats, suggesting that expression of different motor dysfunctions might be related to the receptor profile at corticostriatal synapses. The levels of D1R/NMDAR complexes were unchanged in total striatal membrane proteins, suggesting that the decrease of these species in the PSD is likely to reflect an altered receptor trafficking. In human embryonic kidney 293 cells expressing the D1R/NMDAR, complex costimulation of both D1R and NMDAR, but not individual receptor activation, promoted internalization, suggesting that development of dyskinesias might be related to agonist-mediated down-regulation of the D1R/NMDAR complex at corticostriatal synapses.chemOXIDOPAMINEchemBENSERAZIDE, LEVODOPA DRUG COMBINATIONchemLEVODOPAdiseasePARKINSONIAN DISORDERSdiseaseDYSKINESIA, DRUG-INDUCEDdiseaseBRAIN INJURIESgeneDRD1geneGRIN2BgeneGRIN1action termreactionaction termexpressionixnbenserazide, levodopa drug combination plays a role in or acts as a marker for Dyskinesia, Drug-InducedixnOxidopamine results in decreased expression of GRIN1 protein alternative formixnOxidopamine plays a role in or acts as a marker for Parkinsonian DisordersixnOxidopamine plays a role in or acts as a marker for Brain InjuriesixnLevodopa inhibits the reaction [Oxidopamine results in decreased expression of GRIN2B protein]ixnOxidopamine results in decreased expression of GRIN2B proteinixnLevodopa inhibits the reaction [Oxidopamine results in decreased expression of GRIN1 protein alternative form]ixnLevodopa inhibits the reaction [Oxidopamine results in decreased expression of DRD1 protein]ixnOxidopamine results in decreased expression of DRD1 protein18817789title0Mechanism of the neuroprotective role of coenzyme Q10 with or without L-dopa in rotenone-induced parkinsonism.abstract111Current treatment options for parkinsonism as a neurodegenerative disease are limited and still mainly symptomatic and lack significant disease-modifying effect. Understanding its molecular pathology and finding the cause of dopaminergic cell loss will lead to exploring therapies that could prevent and cure the disease. Mitochondrial dysfunction was found to stimulate releasing of reactive oxygen species (ROS) with subsequent induction of apoptotic neuronal cell death. The aim of the present study was to throw the light on the role of coenzyme Q10 with or without L-dopa in an experimental model of parkinsonism induced by rotenone in rats. The present work showed that rotenone (2.5 mg/kg/day i.p. for 60 days) induced a model of parkinsonism (group II) resembling the basic findings in human characterized by bradykinesia and rigidity manifested as an increase in catalepsy score (detected after 20 days with bad prognosis after 60 days) with marked decrease in striatal dopamine levels. This model confirmed the implication of mitochondrial-apoptotic pathway in the pathogenesis of parkinsonism as there was a decrease in levels of striatal complex I activity and ATP as well as extreme overexpression of the antiapoptotic protein Bcl-2, and also exhibited the role of coenzyme Q10 where its plasma and striatal levels were found to be decreased in comparison to the normal control rats (group I). This proposed pathogenesis was evidenced by the significant correlation between catalepsy score and the neurochemical parameters obtained in the current work. The treated groups started to receive the drug(s) after 20 days from induction of parkinsonism and continued to complete for 60 days. Oral administration of Co Q10 in a low dose 200 mg/kg/day (group III) or a high dose 600 mg/kg/day (group IV), resulted in amelioration of the mitochondrial induced apoptosis by dose-dependent restoration of striatal complex I activity, ATP levels with temperate increase in expression of Bcl-2 as well as decrease in catalepsy score. Although both low and high doses of Co Q10 resulted in significant increase in its plasma and striatal levels, but only the high dose was shown to reach the recommended therapeutic levels. As a current replacement therapy, oral administration of levodopa 10 mg/kg/day (group V), caused symptomatic improvement in the form of reduction of catalepsy score with restoration of striatal dopamine levels, but it did not show any significant effects on either striatal complex I activity, ATP levels or the expression of Bcl-2, pointing to the lack of its disease-modifying role. On the other hand, its administration with high dose of coenzyme Q10 caused the most marked symptomatic improvement in catalepsy score when compared to its administration with low dose of coenzyme Q10, or when compared to either coenzyme Q10 high dose or L-dopa, respectively. Moreover, administration of high dose coenzyme Q10 with L-dopa provided a significant increase in striatal complex I activity, ATP levels and Bcl-2 expression in comparison to group administered coenzyme Q10 low dose with L-dopa, in addition to the significant restoration of striatal dopamine levels and both plasma and striatal Co Q10 levels. Regarding that L-dopa is viewed as a replacement therapy in parkinsonism, it could be concluded that addition of coenzyme Q10 in a high dose in early parkinson''s disease could be recommended based on its proved disease-modifying role on several levels of the proposed mechanisms, including improvement of respiratory chain activity and intervention with neuronal apoptosis. A further research to investigate other apoptosis-targeted compounds will open a new era in the treatment of parkinsonism.chemLEVODOPAchemCOENZYME Q10chemROTENONEdiseaseCATALEPSYdiseasePARKINSON DISEASE, SECONDARYdiseaseHYPOKINESIAdiseaseDISEASE MODELS, ANIMALdiseaseMUSCLE RIGIDITYgeneBCL2action termexpressionixnRotenone plays a role in or acts as a marker for CatalepsyixnRotenone results in increased expression of BCL2 mRNAixnLevodopa has a real or putative therapeutic role towards CatalepsyixnRotenone plays a role in or acts as a marker for Muscle RigidityixnRotenone plays a role in or acts as a marker for Hypokinesiaixncoenzyme Q10 has a real or putative therapeutic role towards CatalepsyixnRotenone plays a role in or acts as a marker for Parkinson Disease, SecondaryixnRotenone plays a role in or acts as a marker for Disease Models, Animalixncoenzyme Q10 results in increased expression of BCL2 mRNA16494910title0Arsenite pretreatment enhances the cytotoxicity of mitomycin C in human cancer cell lines via increased NAD(P)H quinone oxidoreductase 1 expression.abstract149Arsenic is an effective therapeutic agent for the treatment of patients with refractory or relapsed acute promyelocytic leukemia. The use of arsenic for treating solid tumors, particularly in combination with other chemotherapeutic agents, has been extensively studied. Here, we report that arsenite-resistant human lung cancer CL3R15 cells constitutively overexpress NAD(P)H quinone oxidoreductase 1 (NQO1), an enzyme responsible for activation of mitomycin C (MMC), and are more susceptible to MMC cytotoxicity than parental CL3 cells. The effects of arsenite pretreatment on NQO1 induction were examined in CL3, H1299, H460, and MC-T2 cells. Arsenite pretreatment significantly enhanced the expression of NQO1 and susceptibility to MMC in CL3, H1299, and MC-T2 cells, but not in H460 cells that express high endogenous levels of NQO1. Alternatively, arsenic pretreatment reduced adriamycin sensitivity of CL3 cells. Arsenite-mediated MMC susceptibility was abrogated by dicumarol (DIC), an NQO1 inhibitor, indicating that NQO1 is one of the key regulators of arsenite-mediated MMC susceptibility. Various cancer cell lines showed different basal levels of NQO1 activity and a different capacity for NQO1 induction in response to arsenite treatment. However, overall, there was a positive correlation between induced NQO1 activity and MMC susceptibility in cells pretreated with various doses of arsenite. These results suggest that arsenite may increase NQO1 activity and thus enhance the antineoplastic activity of MMC. In addition, our results also showed that inhibition of NQO1 activity by DIC reversed the arsenite resistance of CL3R15 cells.chemARSENITEchemARSENICchemDICUMAROLchemMITOMYCINchemDOXORUBICINdiseaseLEUKEMIA, PROMYELOCYTIC, ACUTEgeneNQO1action termreactionaction termexpressionaction termactivityaction termresponse to substanceixnArsenic has a real or putative therapeutic role towards Leukemia, Promyelocytic, AcuteixnDicumarol inhibits the reaction [[arsenite results in increased expression of NQO1 protein] which results in increased susceptibility to Mitomycin]ixn[arsenite results in increased expression of NQO1 protein] which results in increased susceptibility to Mitomycinixn[arsenite results in increased expression of NQO1 protein] which results in decreased susceptibility to Doxorubicinixnarsenite results in increased expression of NQO1 proteinixnarsenite results in increased expression of NQO1 mRNAixnNQO1 protein results in increased susceptibility to MitomycinixnDicumarol results in decreased activity of NQO1 proteinixnDicumarol inhibits the reaction [NQO1 protein results in decreased susceptibility to arsenite]ixnNQO1 protein results in decreased susceptibility to arsenite20032772title0Oral uridine supplementation antagonizes the peripheral neuropathy and encephalopathy induced by antiretroviral nucleoside analogues.abstract134OBJECTIVE: Peripheral neuropathy and central nervous system neurodegeneration may result from the mitochondrial toxicity of some antiretroviral nucleoside analogues. We investigated whether this neuropathology may be antagonized by uridine supplementation in vivo.
DESIGN: Because of the obvious difficulties in obtaining human neural tissues, the mitochondrial neurotoxicity of the nucleoside analogues was studied in mice.
METHODS: BALB/C mice (7 weeks of age) were fed for 9 weeks with zalcitabine (13 mg/kg per day) or zidovudine (100 mg/kg per day) with or without mitocnol (340 mg/kg per day), a dietary supplement with high uridine bioavailability. Hippocampal and sciatic nerve mitochondria were analyzed.
RESULTS: Zalcitabine and to a lesser extent zidovudine induced a significant peripheral neuropathy and encephalopathy with disrupted mitochondrial ultrastructure, depleted mitochondrial DNA, reduced levels of cytochrome c oxidase activity and diminished expression of mitochondrial DNA-encoded cytochrome c oxidase subunit I. Mitocnol had no intrinsic effects but attenuated or fully normalized all measured disorder of the peripheral and central nervous system.
CONCLUSION: Zidovudine and zalcitabine induce a mitochondrial disorder in the peripheral and central nervous system, both of which are antagonized by uridine supplementation.chemZIDOVUDINEchemZALCITABINEchemURIDINEdiseasePERIPHERAL NERVOUS SYSTEM DISEASESdiseaseMITOCHONDRIAL ENCEPHALOPATHYgeneCOX1action termreactionaction termexpressionixnZalcitabine results in decreased expression of COX1 proteinixnUridine inhibits the reaction [Zalcitabine results in decreased expression of COX1 protein]ixnUridine inhibits the reaction [Zidovudine results in decreased expression of COX1 protein]ixnZalcitabine plays a role in or acts as a marker for Mitochondrial encephalopathyixnUridine has a real or putative therapeutic role towards Peripheral Nervous System DiseasesixnZidovudine plays a role in or acts as a marker for Peripheral Nervous System DiseasesixnZidovudine plays a role in or acts as a marker for Mitochondrial encephalopathyixnUridine has a real or putative therapeutic role towards Mitochondrial encephalopathyixnZalcitabine plays a role in or acts as a marker for Peripheral Nervous System DiseasesixnZidovudine results in decreased expression of COX1 protein19815945title0Bradykinin receptor antagonists and cyclooxygenase inhibitors in vincristine- and streptozotocin-induced hyperalgesia.abstract119Pain that accompanies neuropathy is difficult to treat. Analgesics administered as monotherapies possess low activities in relieving this kind of pain. The effect of the simultaneous administration of indomethacin (a preferential inhibitor of cyclooxygenase-1; COX-1) or celecoxib (a relatively selective inhibitor of cyclooxygenase-2; COX-2), with selective antagonists of bradykinin(2) (B(2)) bradykinin(1) (B(1)) receptors (HOE 140 or des-Arg(10)-HOE 140) on the alleviation of diabetic and toxic neuropathic pain was investigated. Pretreatment with indomethacin (0.1 mg/kg, sc) increased the antihyperalgesic activity of low daily doses of HOE 140 or des-Arg(10)HOE 140 (70 nmol/kg, ip) in a diabetic (streptozotocin(STZ)-induced) neuropathy/hyperalgesia experimental model. Premedication with celecoxib before HOE 140 or des-Arg(10)HOE 140 administration resulted in a gradual reduction of STZ hyperalgesia. Furthermore, on days 23-24, almost complete abolishment of STZ hyperalgesia was observed. After cessation of drug administration, hyperalgesia quickly returned to the baseline threshold. The results of this study suggest that inhibitors of cyclooxygenases can increase the antihyperalgesic activity of selective antagonists of B(2) and B(1) receptors in diabetic and toxic neuropathic pain models. These observations may be clinically relevant.chemSTREPTOZOCINchemINDOMETHACINchemHOE 140, DESARG(10)-chemICATIBANTchemVINCRISTINEchemCELECOXIBdiseasePERIPHERAL NERVOUS SYSTEM DISEASESdiseaseHYPERALGESIAdiseaseDIABETIC NEUROPATHIESgeneBDKRB1geneBDKRB2ixnBDKRB1 plays a role in or acts as a marker for HyperalgesiaixnVincristine plays a role in or acts as a marker for Peripheral Nervous System DiseasesixnIndomethacin has a real or putative therapeutic role towards HyperalgesiaixnHOE 140, desArg(10)- has a real or putative therapeutic role towards HyperalgesiaixnStreptozocin plays a role in or acts as a marker for Diabetic NeuropathiesixnVincristine plays a role in or acts as a marker for HyperalgesiaixnBDKRB2 plays a role in or acts as a marker for HyperalgesiaixnStreptozocin plays a role in or acts as a marker for Hyperalgesiaixnicatibant has a real or putative therapeutic role towards Hyperalgesiaixncelecoxib has a real or putative therapeutic role towards Hyperalgesia20651248title0Resveratrol inhibits renal fibrosis in the obstructed kidney: potential role in deacetylation of Smad3.abstract104Transforming growth factor-beta1 (TGF-beta1) promotes tissue fibrosis through the Smad3 signaling pathway. While phosphorylation is known to regulate Smad3 function, recent in vitro studies have suggested that acetylation may also regulate Smad3 function. This study investigated Smad3 acetylation in renal fibrosis. TGF-beta1 stimulation of renal fibroblasts and tubular epithelial cells induced Smad3 acetylation and phosphorylation. Resveratrol, an activator of the Nicotinamide adenine dinucleotide (NAD) dependent protein deacetylase SIRT1, reversed acetylation but not phosphorylation of Smad3 and inhibited TGF-beta1-induced up-regulation of collagen IV and fibronectin mRNA levels. Knockdown of SIRT1 expression abolished the inhibitory effect of resveratrol, and co-immunoprecipitation studies provide direct evidence of an interaction between acetylated Smad3 and SIRT1. The role of Smad3 acetylation in renal fibrosis was then examined in the unilateral ureteric obstruction (UUO) model. Immunoprecipitation studies showed acetylation and phosphorylation of Smad3 by day 2 UUO, which was sustained to day 7 in association with development of interstitial fibrosis. Resveratrol inhibited acetylation but not phosphorylation of Smad3 at day 2 UUO, and resveratrol treatment inhibited interstitial fibrosis at day 7 UUO. In conclusion, these studies support a pathological role for Smad3 acetylation in renal fibrosis and suggest that deacetylation of Smad3 may be a novel therapeutic target for fibrotic disease.chemRESVERATROLdiseaseFIBROSISdiseaseKIDNEY DISEASESgeneSMAD3geneTGFB1geneSIRT1action termreactionaction termacetylationaction termactivityaction termresponse to substanceixnresveratrol results in increased activity of SIRT1 proteinixnSIRT1 plays a role in or acts as a marker for Fibrosisixnresveratrol inhibits the reaction [TGFB1 protein results in increased acetylation of SMAD3 protein]ixnSIRT1 protein affects the reaction [resveratrol inhibits the reaction [TGFB1 protein results in increased acetylation of SMAD3 protein]]ixnresveratrol results in decreased acetylation of SMAD3 proteinixnSIRT1 protein affects the susceptibility to resveratrolixnresveratrol results in decreased susceptibility to TGFB1 proteinixnresveratrol results in decreased acetylation of SMAD3 proteinixnresveratrol has a real or putative therapeutic role towards Kidney Diseasesixnresveratrol has a real or putative therapeutic role towards Fibrosis17962980title0Induction of full-length survival motor neuron by polyphenol botanical compounds.abstract82The loss of survival motor neuron-1 (SMN1) is responsible for the development of the neurodegenerative disorder spinal muscular atrophy (SMA). A nearly identical copy of SMN1 is present on the same chromosomal region called SMN2. While SMN2 encodes a normal SMN protein, the majority of SMN2-derived transcripts are alternatively spliced, resulting in a truncated protein that lacks the 16 amino acids encoded by SMN exon 7. Numerous studies have shown that the SMN2-derived protein product, called SMNDelta7, is unstable and dysfunctional. Therefore, identifying molecules that stimulate full-length SMN expression from the SMN2 gene could lead to the development of effective therapies for a broad range of SMA patient populations. Polyphenol compounds have been shown to provide benefit in varied genetic disease contexts. For example, epigallocatechin galate (EGCG) was found to correct aberrant alternative mRNA splicing in familiar dysautonomia (FD). A series of polyphenols were screened and a subset was shown to increase full-length SMN expression from SMN2. Curcumin, EGCG, and resveratrol increased exon 7 inclusion of SMN2 transcripts in transient reporter assays. In SMA patient fibroblasts, these compounds stimulated the production of full-length SMN RNA and protein as well as the formation of SMN-containing nuclear gems. Collectively, these compounds elevated total SMN concentrations in SMA patient fibroblasts, potentially through the modulation of SMN2 exon 7 alternative splicing.chemEPIGALLOCATECHIN GALLATEchemCURCUMINchemRESVERATROLdiseaseMUSCULAR ATROPHY, SPINALgeneSMN2action termexpressionaction termsplicingixnresveratrol has a real or putative therapeutic role towards Muscular Atrophy, Spinalixnepigallocatechin gallate has a real or putative therapeutic role towards Muscular Atrophy, SpinalixnCurcumin has a real or putative therapeutic role towards Muscular Atrophy, Spinalixnresveratrol affects the splicing of and results in increased expression of SMN2 mRNA alternative formixnCurcumin affects the splicing of and results in increased expression of SMN2 mRNA alternative formixnepigallocatechin gallate affects the splicing of and results in increased expression of SMN2 mRNA alternative formixnresveratrol results in increased expression of SMN2 proteinixnCurcumin results in increased expression of SMN2 proteinixnepigallocatechin gallate results in increased expression of SMN2 protein16514058title0Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin.abstract111Bradykinin (BK) liberates nitric oxide, prostacyclin, and tissue plasminogen activator from endothelial cells. We hypothesized that BK B2 receptor knockout (KO) mice (BKB2R(-/-)) have increased thrombosis risk. Paradoxically, the BKB2R(-/-) mice have long bleeding times and delayed carotid artery thrombosis, 78 +/- 6.7 minutes, versus 31 +/- 2.7 minutes in controls. The mechanism(s) for thrombosis protection was sought. In BKB2R(-/-) plasma coagulation, fibrinolysis and anticoagulant proteins are normal except for an increased prekallikrein and decreased factor XI. BKB2R(-/-) mice have elevated BK 1-5 (160 +/- 75 fmol/mL, vs 44 +/- 29 fmol/mL in controls) and angiotensin II (182 +/- 41 pg/mL, vs 49 +/- 7 pg/mL in controls). Ramipril treatment shortens vessel occlusion time. BKB2R(-/-) mice have elevated plasma 6-keto-PGF1alpha (666 +/- 232 ng/mL, vs 23 +/- 5.3 ng/mL in controls) and serum nitrate (61 +/- 5.3 microM, vs 24 +/- 1.8 microM in controls). Treatment with L-NAME (NG-mono-methyl-L-arginine ester) or nimesulide shortens the thrombosis time. BKB2R(-/-) mice have increased angiotensin receptor 2 (AT2R) mRNA and protein expression. Treatment with an AT2R antagonist, PD123 319, normalizes the thrombosis time and nitrate and 6-keto-PGF1alpha. The long bleeding times in BKB2R(-/-) mice also correct with L-NAME and nimesulide therapy. In BKB2R(-/-) mice, angiotensin II binding to an overexpressed AT2R promotes thromboprotection by elevating nitric oxide and prostacyclin. These investigations indicate a pathway for thrombosis risk reduction via the plasma kallikrein/kinin and renin angiotensin systems.chemICATIBANTchemEPOPROSTENOLchemPD 123319chem6-KETOPROSTAGLANDIN F1 ALPHAchemNITRIC OXIDEdiseaseTHROMBOSISdiseaseHEMORRHAGEgeneKNG1geneBDKRB2action termreactionaction termsecretionaction termbindingaction termactivityaction termabundanceixnicatibant plays a role in or acts as a marker for ThrombosisixnBDKRB2 affects the abundance of 6-Ketoprostaglandin F1 alphaixnBDKRB2 plays a role in or acts as a marker for ThrombosisixnPD 123319 affects the reaction [BDKRB2 affects the abundance of 6-Ketoprostaglandin F1 alpha]ixnicatibant binds to and results in decreased activity of BDKRB2 proteinixnBDKRB2 plays a role in or acts as a marker for HemorrhageixnPD 123319 affects the reaction [KNG1 affects the abundance of Nitric Oxide]ixnKNG1 affects the abundance of Nitric OxideixnKNG1 affects the secretion of Epoprostenol19449198title0Capsaicin alleviates the imbalance in xenobiotic metabolizing enzymes and tumor markers during experimental lung tumorigenesis.abstract128Lung cancer is currently a leading cause of death all over the world. Environmental risk factors, particularly genotoxic chemicals such as polycyclic aromatic hydrocarbons (PAH), are likely to account for a much higher mortality. Xenobiotic metabolizing enzymes are potentially chief determinants in both the susceptibility to the mutagenic effects of chemical carcinogens and in the response of tumors to chemotherapy. The well-known carcinogen benzo(a)pyrene (B(a)P) of PAH family was given orally (50 mg/kg body weight) to induce lung cancer in Swiss albino mice. B(a)P induction altered the levels of cytochromes (P450, b5), activities of phase I biotransformation enzymes (NADPH-cytochrome P450 reductase, NADH-cytochrome b5 reductase and epoxide hydrolase), phase II enzymes (glutathione-S-transferase, UDP-glucuronyl transferase and DT-diaphorase), and the levels of serum tumor markers. Treatment with capsaicin (CAP) (10 mg/kg body weight) to the lung carcinoma mice restored back the activities of phase I and II biotransformation enzymes and the levels of tumor markers to near normalcy. The above findings were substantiated by immunoblotting and immunohistochemical analysis of cytochrome P450 1A1 (CYP1A1) in the lung tissues. Our present study unravels that CAP can effectively detoxify the carcinogens which discloses its anti-carcinogenic effect during experimental lung cancer.chemCAPSAICINchemBENZO(A)PYRENEdiseaseLUNG NEOPLASMSgeneNQO1genePORgeneENO2geneCYP1A1action termreactionaction termexpressionaction termactivityixnCapsaicin inhibits the reaction [Benzo(a)pyrene results in increased expression of ENO2 protein]ixnBenzo(a)pyrene results in increased expression of POR proteinixnCapsaicin inhibits the reaction [Benzo(a)pyrene results in increased expression of POR protein]ixnBenzo(a)pyrene results in increased expression of CYP1A1 proteinixnCapsaicin inhibits the reaction [Benzo(a)pyrene results in increased expression of CYP1A1 protein]ixnBenzo(a)pyrene plays a role in or acts as a marker for Lung NeoplasmsixnBenzo(a)pyrene results in decreased activity of NQO1 proteinixnCapsaicin inhibits the reaction [Benzo(a)pyrene results in decreased activity of NQO1 protein]ixnBenzo(a)pyrene results in increased expression of ENO2 protein9765069title0Glutamine transaminase K intranephron localization in rats determined by urinary excretion after treatment with segment-specific nephrotoxicants.abstract146Glutamine transaminase K(GTK) excretion assessed in urine and by kidney histology was evaluated in rats after single treatment with 1.0 mg/kg i.p. of mercuric chloride, 100 mg/kg i.p. of hexachloro-1:3-butadiene (both S3, pars recta, segment-specific nephrotoxicants) and 25 mg/kg s.c. of potassium dichromate (S1-S2, pars convoluta, segment-specific nephrotoxicant). The aim was to correlate segment-specific injury and enzyme excretion in order to assess, using non-vasive methods, localization of GTK along the proximal tubule. Mercuric chloride and hexachloro-1:3-butadiene produced early focal damage in the pars recta (focal necrosis was shown 10 h after treatment, and diffuse necrosis appeared later at 34 and 24 h after treatment). Changes of the pars convoluta were occasional and delayed (72 h after treatment for both substances). On the contrary, potassium dichromate induced damage of the pars convoluta (vacuolar degeneration and focal necrosis were evident 24 h and 48 h after treatment, respectively), whereas the pars recta was affected later (focal vacuolar degeneration was observed 72 h after treatment). Increase urinary GTK excretion was early after treatment with mercuric chloride and hexachloro-1:3-butadiene (significant increase was observed within 10 h), with a peak for both substances 24 h after treatment, in agreement with the necrosis of the pars recta. Potassium dichromate induced a significant increase of enzyme excretion in urine also 24 h after injection, according to histological features showing vacuolar degeneration of the pars convoluta; the peak of excretion was reached 48 h after treatment (delay was due, probably, to s.c. administration). The results show that GTK increased in urine after treatment with S3 and S1-S2 specific nephrotoxicants; the combination of histological examination and urinary enzyme supports the evidence that the enzyme is distributed along the whole of the proximal tubule.chemPOTASSIUM DICHROMATEchemMERCURIC CHLORIDEchemHEXACHLOROBUTADIENEdiseaseNECROSISdiseaseKIDNEY TUBULAR NECROSIS, ACUTEgeneCCBL1action termexpressionixnhexachlorobutadiene plays a role in or acts as a marker for NecrosisixnPotassium Dichromate plays a role in or acts as a marker for Kidney Tubular Necrosis, AcuteixnPotassium Dichromate plays a role in or acts as a marker for NecrosisixnMercuric Chloride results in increased expression of CCBL1 proteinixnMercuric Chloride plays a role in or acts as a marker for Kidney Tubular Necrosis, Acuteixnhexachlorobutadiene results in increased expression of CCBL1 proteinixnhexachlorobutadiene plays a role in or acts as a marker for Kidney Tubular Necrosis, AcuteixnMercuric Chloride plays a role in or acts as a marker for NecrosisixnPotassium Dichromate results in increased expression of CCBL1 protein19859697title0Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys: kappa opioid and serotonergic mechanisms.abstract124RATIONALE: Kappa agonists can attenuate reinstatement of cocaine-seeking behavior induced by cocaine priming. The mechanisms underlying this effect have not been characterized fully but may have a serotonergic component as kappa agonists also increase the release of serotonin (5-hydroxytryptamine, 5-HT).
OBJECTIVES: This study investigated the role of kappa opioid receptor and 5-HT mechanisms in kappa agonist-induced attenuation of cocaine priming in monkeys.
METHODS: Squirrel monkeys were trained to self-administer cocaine (0.18-0.3 mg/kg/injection) under a second-order schedule in which drug seeking was maintained jointly by cocaine injections and a cocaine-paired visual stimulus. In extinction sessions, saline was substituted for cocaine, and the cocaine-paired stimulus was omitted. During test sessions, only saline was available for self-administration, and response-contingent presentations of the cocaine-paired stimulus were restored.
RESULTS: Priming injections of cocaine (0.1-1.0 mg/kg) induced reinstatement of drug seeking. Maximal levels of responding were similar to those maintained by active cocaine self-administration. Pretreatment with the kappa agonists enadoline (0.01 mg/kg) and spiradoline (0.3 mg/kg) or the 5-HT transport inhibitors fluoxetine (5.6 mg/kg) and citalopram (10.0 mg/kg) attenuated the priming effects of cocaine, shifting the cocaine dose-response function rightward and downward. Inhibition of cocaine-induced reinstatement of drug seeking by spiradoline and fluoxetine was reversed by R(+)8-hydroxy-2-(di-n-propylamino)tetralin (0.03 mg/kg), a 5HT(1A) agonist that inhibits 5-HT release. The effects of spiradoline also were reversed by the kappa antagonist nor-binaltorphimine (10.0 mg/kg).
CONCLUSIONS: Results suggest that the capacity of kappa opioid agonists to increase extracellular 5-HT levels may at least partially underlie kappa agonist-induced modulation of cocaine seeking.chemCITALOPRAMchemCOCAINEchem8-HYDROXY-2-(DI-N-PROPYLAMINO)TETRALINchemNORBINALTORPHIMINEchemENADOLINEchemSPIRADOLINEchemFLUOXETINEdiseaseCOCAINE-RELATED DISORDERSgeneHTR1AgeneOPRK1action termbindingaction termactivityixn8-Hydroxy-2-(di-n-propylamino)tetralin binds to and results in increased activity of HTR1A proteinixnenadoline binds to and results in increased activity of OPRK1 proteinixnnorbinaltorphimine binds to and results in decreased activity of OPRK1 proteinixnCocaine plays a role in or acts as a marker for Cocaine-Related Disordersixnspiradoline has a real or putative therapeutic role towards Cocaine-Related DisordersixnCitalopram has a real or putative therapeutic role towards Cocaine-Related Disordersixnspiradoline binds to and results in increased activity of OPRK1 proteinixnenadoline has a real or putative therapeutic role towards Cocaine-Related DisordersixnFluoxetine has a real or putative therapeutic role towards Cocaine-Related Disorders19566839title0Rosiglitazone-induced myocardial protection against ischaemia-reperfusion injury is mediated via a phosphatidylinositol 3-kinase/Akt-dependent pathway.abstract1521. Rosiglitazone is widely used in the treatment of Type 2 diabetes. However, in recent years it has become evident that the therapeutic effects of peroxisome proliferator-activated receptor gamma ligands reach far beyond their use as insulin sensitizers. Recently, the ability of rosiglitazone pretreatment to induce cardioprotection following ischaemia-reperfusion (I/R) has been well documented; however, the protective mechanisms have not been elucidated. In the present study, examined the role of the phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway in rosiglitazone cardioprotection following I/R injury. 2. Mice were pretreated with 3 mg/kg per day rosiglitazone for 14 days before hearts were subjected to ischaemia (30 min) and reperfusion (2 h). Wortmannin (1.4 mg/kg, i.p.), an inhibitor of PI3-K, was administered 10 min prior to myocardial I/R. Then, activation of the PI3-K/Akt/glycogen synthase kinase (GSK)-3alpha signalling pathway was examined. The effects of PI3-K inhibition on rosiglitazone-induced cardioprotection were also evaluated. 3. Compared with control rats, the ratio of infarct size to ischaemic area (area at risk) and the occurrence of sustained ventricular fibrillation in rosiglitazone-pretreated rats was significantly reduced (P < 0.05). Rosiglitazone pretreatment attenuated cardiac apoptosis, as assessed by ELISA to determine cardiomyocyte DNA fragmentation. Rosiglitazone pretreatment significantly increased levels of phosphorylated (p-) Akt and p-GSK-3alpha in the rat myocardium. Pharmacological inhibition of PI3-K by wortmannin markedly abolished the cardioprotection induced by rosiglitazone. 4. These results indicate that rosiglitazone-induced cardioprotection in I/R injury is mediated via a PI3-K/Akt/GSK-3alpha-dependent pathway. The data also suggest that modulation of PI3-K/Akt/GSK-3alpha-dependent signalling pathways may be a viable strategy to reduce myocardial I/R injury.chemWORTMANNINchemROSIGLITAZONEdiseaseTACHYCARDIA, VENTRICULARdiseaseMYOCARDIAL INFARCTIONdiseaseMYOCARDIAL REPERFUSION INJURYdiseaseVENTRICULAR PREMATURE COMPLEXESgeneGSK3Baction termreactionaction termphosphorylationixnrosiglitazone has a real or putative therapeutic role towards Tachycardia, Ventricularixnrosiglitazone has a real or putative therapeutic role towards Ventricular Premature Complexesixnrosiglitazone has a real or putative therapeutic role towards Myocardial Infarctionixnrosiglitazone results in increased phosphorylation of GSK3B proteinixnwortmannin inhibits the reaction [rosiglitazone results in increased phosphorylation of GSK3B protein]ixnrosiglitazone has a real or putative therapeutic role towards Myocardial Reperfusion Injury21761357title0In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer.abstract186Diethylstilbestrol (DES) and bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that epigenetic alterations would precede the increased risk of breast neoplasia after in utero exposure to endocrine disruptors. Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that has been linked to breast cancer risk and epigenetic regulation of tumorigenesis. We examined the effect of BPA and DES on EZH2 expression and function in MCF-7 cells and in mammary glands of mice exposed in utero. DES and BPA treatment approximated human exposure. EZH2 functional activity was assessed by measuring histone H3 trimethylation. Treatment of MCF-7 cells with DES or BPA led to a 3- and 2-fold increase in EZH2 mRNA expression, respectively (p < 0.05) as well as increased EZH2 protein expression. Mice exposed to DES in utero showed a >2-fold increase in EZH2 expression in adult mammary tissue compared with controls (p < 0.05). EZH2 protein was elevated in mammary tissue of mice exposed to DES or BPA. Histone H3 trimethylation was increased in MCF-7 cells treated with BPA or DES. Similarly, mice exposed to BPA or DES in utero showed increased mammary histone H3 trimethylation. Developmental programming of EZH2 is a novel mechanism by which in utero exposure to endocrine disruptors leads to epigenetic regulation of the mammary gland.chemDIETHYLSTILBESTROLchemBISPHENOL AdiseasePRENATAL EXPOSURE DELAYED EFFECTSgeneEZH2action termexpressionixnDiethylstilbestrol results in increased expression of EZH2 mRNAixnbisphenol A results in increased expression of EZH2 mRNAixnDiethylstilbestrol results in increased expression of EZH2 proteinixnbisphenol A results in increased expression of EZH2 proteinixnDiethylstilbestrol plays a role in or acts as a marker for Prenatal Exposure Delayed EffectsixnDiethylstilbestrol results in increased expression of EZH2 proteinixnbisphenol A results in increased expression of EZH2 proteinixnDiethylstilbestrol results in increased expression of EZH2 mRNAixnbisphenol A plays a role in or acts as a marker for Prenatal Exposure Delayed Effects20184326title0Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate.abstract197Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.chemMK 6892chemNIACINchemFATTY ACIDS, NONESTERIFIEDdiseaseFLUSHINGgeneNIACR1geneHCAR2geneGPR109Aaction termbindingaction termactivityaction termabundanceixnMK 6892 binds to and results in increased activity of NIACR1 proteinixnMK 6892 binds to and results in increased activity of NIACR1 proteinixnNiacin plays a role in or acts as a marker for FlushingixnMK 6892 plays a role in or acts as a marker for Flushingixn[MK 6892 binds to and results in increased activity of NIACR1 protein] which results in decreased abundance of Fatty Acids, Nonesterifiedixn[MK 6892 binds to and results in increased activity of NIACR1 protein] which results in decreased abundance of Fatty Acids, Nonesterifiedixn[MK 6892 binds to and results in increased activity of GPR109A protein] which results in decreased abundance of Fatty Acids, NonesterifiedixnMK 6892 binds to and results in increased activity of HCAR2 proteinixnMK 6892 binds to and results in increased activity of GPR109A protein20307515title0Modulation of PPAR-gamma by telmisartan protects the heart against myocardial infarction in experimental diabetes.abstract115Telmisartan, an angiotensin II-receptor blocker (ARB), is a partial agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). We investigated whether telmisartan improved the pathophysiology of myocardial infarction in diabetes partially through the PPAR-gamma pathway by assessing a variety of indices, e.g., hemodynamic, biochemical, histoarchitectural changes, and apoptosis. Diabetes was induced by a single dose of streptozotocin (70 mg/kg, IP). Diabetic rats received either telmisartan (10 mg/kg/day, orally), the PPAR-gamma antagonist GW9662 (1 mg/kg/day, IP), or both for 14 days with concurrent administration of isoproterenol (85 mg/kg, SC) on days 13 and 14. Compared with diabetic controls, diabetic rats with myocardial infarction exhibited altered hemodynamic profiles and reduction in the activities of creatine kinase-MB isoenzyme, lactate dehydrogenase, superoxide dismutase, catalase, and glutathione level along with increased level of malondialdehyde in the heart. Further, diabetic animals with myocardial infarction exhibited increased myonecrosis, edema, and apoptotic cell death. Treatment with telmisartan significantly improved the redox status of the myocardium with subsequent cardiac functional recovery. However, significant effects were lowered in animals treated with telmisartan plus GW9662. Telmisartan markedly inhibited Bax expression, TUNEL-positive cells, myonecrosis, and edema. On the other hand, administration of telmisartan plus GW9662 did not elicit the same effects, nor did they increase Bcl-2 protein expression in isoproterenol-induced myocardially infarcted diabetic rats when administered concomitantly or individually. Moreover, down-regulated PPAR-gamma expression in myocardially infarcted diabetic hearts was increased by telmisartan treatment. In addition to class effects of ARBs, telmisartan reduces oxidative stress and apoptosis and improves cardiac function via the PPAR-gamma pathway.chem2-CHLORO-5-NITROBENZANILIDEchemISOPROTERENOLchemSTREPTOZOCINchemTELMISARTANdiseaseMYOCARDIAL INFARCTIONdiseaseDIABETES MELLITUS, EXPERIMENTALgenePPARGgeneBAXaction termexpressionixntelmisartan results in decreased expression of BAX proteinixntelmisartan has a real or putative therapeutic role towards Myocardial Infarctionixntelmisartan results in increased expression of PPARG proteinixnStreptozocin plays a role in or acts as a marker for Diabetes Mellitus, ExperimentalixnIsoproterenol plays a role in or acts as a marker for Myocardial Infarction22001142title0Tetrandrine down-regulates ERK/NF- B signaling and inhibits activation of mesangial cells.abstract91OBJECTIVES: Tetrandrine (TET), a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra S. Moore of the Menispermaceae, possesses anti-inflammatory activity. We examined the effect of tetrandrine on interleukin-1 (IL-1 )-provoked inflammatory response in mesangial cells.
MATERIALS AND METHODS: Primary rat mesangial cells (PRMCs) were treated with IL-1 to induce inflammation to resemble glomerulonephritis. Cell viability, morphology and NO production were evaluated. Western blotting was applied for expression of matrix metalloproteinase-9 (MMP-9), inducible NO synthase (iNOS), extracellular signal-regulated kinase (ERK) and NF- B-related molecules. Electrophoretic mobility shift assay was performed to examine the DNA-binding activity of NF- B.
RESULTS: TET, at concentrations up to 10 g/ml, had no significant effect on viability of PRMCs. At non-toxic concentrations, TET inhibited expression of phosphorylated ERK as well as phosphorylated IKK, enhanced degradation of I B and reduced the DNA-binding activity of NF- B in IL-1 -primed PRMCs, suggesting an inhibitory effect on ERK/NF- B signaling. TET attenuated the IL-1 -provoked expression of iNOS and release of NO. Moreover, both the protein expression and gelatinase activity of MMP-9, but not MMP-2, were markedly suppressed by TET.
SIGNIFICANCE: TET down-regulated ERK/NF- B signaling and inhibited the expression of inflammatory mediators NO and MMP-9. Since these mediators appear to activate mesangial cells, TET may play an important role in prevention of glomerulonephritis.chemPD 98059chemTETRANDRINEdiseaseINFLAMMATIONgeneNOS2geneMAPK3geneMAPK1geneIL1BgeneCHUKgeneMMP9geneNFKBIAaction termexpressionaction termreactionaction termdegradationaction termphosphorylationaction termactivityixnPD 98059 inhibits the reaction [IL1B protein results in increased phosphorylation of NFKBIA protein]ixnIL1B plays a role in or acts as a marker for Inflammationixntetrandrine inhibits the reaction [IL1B protein results in increased phosphorylation of MAPK1 protein]ixntetrandrine inhibits the reaction [IL1B protein results in increased phosphorylation of MAPK3 protein]ixnPD 98059 inhibits the reaction [IL1B protein results in increased phosphorylation of MAPK1 protein]ixnPD 98059 inhibits the reaction [IL1B protein results in increased phosphorylation of MAPK3 protein]ixntetrandrine inhibits the reaction [IL1B protein results in increased expression of NOS2 protein]ixntetrandrine inhibits the reaction [IL1B protein results in increased phosphorylation of CHUK protein]ixntetrandrine inhibits the reaction [IL1B protein results in increased phosphorylation of and results in increased degradation of NFKBIA protein]ixntetrandrine inhibits the reaction [IL1B protein results in increased expression of and results in increased activity of MMP9 protein]18374380title0Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity.abstract62Previous experiments showed that treatment of mice and rats with thioacetamide (TAA) induced liver cell damage, fibrosis and/or cirrhosis, associated with increased oxidative stress and activation of hepatic stellate cells. Some experiments suggest that CYP2E1 may be involved in the metabolic activation of TAA. However, there is no direct evidence on the role of CYP2E1 in TAA-mediated hepatotoxicity. To clarify this, TAA-induced hepatotoxicity was investigated using Cyp2e1-null mice. Male wild-type and Cyp2e1-null mice were treated with TAA (200 mg/kg of body weight, single, i.p.) at 6 weeks of age, and hepatotoxicity examined 24 and 48 h after TAA treatment. Relative liver weights of Cyp2e1-null mice were significantly different at 24 h compared to wild-type mice (p<0.01). Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in Cyp2e1-null mice were significantly different at both time points compared to wild-type mice (p<0.01). Histopathological examination showed Cyp2e1-null mice represented no hepatototoxic lesions, in clear contrast to severe centriobular necrosis, inflammation and hemorrhage at both time points in wild-type mice. Marked lipid peroxidation was also only limited to wild-type mice (p<0.01). Similarly, TNF-alpha, IL-6 and glutathione peroxidase mRNA expression in Cyp2e1-null mice did not significantly differ from the control levels, contrasting with the marked alteration in wild-type mice (p<0.01). Western blot analysis further revealed no increase in iNOS expression in Cyp2e1-null mice. These results reveal that CYP2E1 mediates TAA-induced hepatotoxicity in wild-type mice as a result of increased oxidative stress.chemTHIOACETAMIDEdiseaseLIVER DISEASESgeneIL6geneCYP2E1geneNOS2geneGPX1geneTNFaction termreactionaction termexpressionaction termresponse to substanceixnThioacetamide plays a role in or acts as a marker for Liver DiseasesixnCYP2E1 protein results in increased susceptibility to ThioacetamideixnThioacetamide results in increased expression of TNF mRNAixnThioacetamide results in increased expression of IL6 mRNAixnThioacetamide results in decreased expression of GPX1 mRNAixnThioacetamide results in increased expression of NOS2 proteinixnCYP2E1 protein affects the reaction [Thioacetamide results in increased expression of TNF mRNA]ixnCYP2E1 protein affects the reaction [Thioacetamide results in increased expression of IL6 mRNA]ixnCYP2E1 protein affects the reaction [Thioacetamide results in decreased expression of GPX1 mRNA]ixnCYP2E1 protein affects the reaction [Thioacetamide results in increased expression of NOS2 protein]11012881title0Nephrin in experimental glomerular disease.abstract44BACKGROUND: The recently identified gene NPHS1 with its mutations causing congenital nephrotic syndrome of the Finnish type (CNF) is highly promising in providing new understanding of pathophysiology of proteinuria. Earlier we cloned a rat NPHS1 homologue, as well as characterized and raised antibodies to the respective protein product nephrin.
METHODS: Changes in the expression levels of nephrin-specific mRNA in commonly used experimental models of proteinuria were examined using semiquantitative reverse transcription-polymerase chain reaction, immunofluorescence, and immunoelectron microscopy (IEM) of nephrin.
RESULTS: Notably, a 40% down-regulation of the nephrin-specific mRNA of cortical kidney was seen already at day 3 after induction of the puromycin aminonucleoside nephrosis (PAN), while no major elevation of urinary protein secretion was seen at this stage. A further decrease of 80% of nephrin message was seen at the peak of proteinuria at day 10. A similar decrease of up to 70% from the basal levels was seen in mercuric chloride-treated rats. Changes in the protein expression paralleled those of the mRNA in indirect immunofluorescence. Interestingly, a remarkable plasmalemmal dislocation from the normal expression site at the interpodocyte filtration slits could be observed in IEM.
CONCLUSIONS: Nephrin appears to be an important causative molecule of proteinuria and shows a remarkable redistribution from the filtration slits to the podocyte plasma membrane, especially in PAN.chemPROBUCOLchemPUROMYCIN AMINONUCLEOSIDEchemMERCURIC CHLORIDEdiseaseNEPHROSIS, CONGENITALdiseaseNEPHROTIC SYNDROMEgeneNPHS1action termreactionaction termexpressionixnMercuric Chloride results in decreased expression of NPHS1 mRNAixnPuromycin Aminonucleoside promotes the reaction [Mercuric Chloride results in decreased expression of NPHS1 mRNA]ixnPuromycin Aminonucleoside plays a role in or acts as a marker for Nephrotic SyndromeixnPuromycin Aminonucleoside results in decreased expression of NPHS1 mRNAixnProbucol results in increased expression of NPHS1 mRNAixnProbucol does not affect the reaction [Puromycin Aminonucleoside promotes the reaction [Mercuric Chloride results in decreased expression of NPHS1 mRNA]]ixnPuromycin Aminonucleoside results in decreased expression of NPHS1 proteinixnNPHS1 plays a role in or acts as a marker for Nephrosis, congenitalixnMercuric Chloride promotes the reaction [Puromycin Aminonucleoside results in decreased expression of NPHS1 protein]17890855title0Angiotensin-(1-7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats.abstract117BACKGROUND/AIM: We examined the influence of chronic treatment with angiotensin-(1-7) [Ang-(1-7)] on renox (renal NADPH oxidase, NOX-4) and the development of renal dysfunction in streptozotocin-treated spontaneously hypertensive rats (diabetic SHR).
METHODS: Mean arterial pressure, urinary protein and vascular responsiveness of the isolated renal artery to vasoactive agonists were studied in vehicle- or Ang-(1-7)-treated SHR and diabetic SHR.
RESULTS: Ang-(1-7) decreased the elevated levels of renal NADPH oxidase (NOX) activity and attenuated the activation of NOX-4 gene expression in the diabetic SHR kidney. Ang-(1-7) treatment increased sodium excretion but did not affect mean arterial pressure in diabetic SHR. There was a significant increase in urinary protein (266 +/- 22 mg/24 h) in the diabetic compared to control SHR (112 +/- 13 mg/24 h) and treatment of diabetic SHR with Ang-(1-7) reduced the degree of proteinuria (185 +/- 23 mg/24 h, p < 0.05). Ang-(1-7) treatment also attenuated the diabetes-induced increase in renal vascular responsiveness to endothelin-1, norepinephrine, and angiotensin II in SHR, but significantly increased the vasodilation of the renal artery of SHR and diabetic SHR to the vasodilator agonists.
CONCLUSION: These results suggest that treatment with Ang-(1-7) constitutes a potential therapeutic strategy to alleviate NOX-mediated oxidative stress and to reduce renal dysfunction in diabetic hypertensive rats.chemSTREPTOZOCINdiseaseDIABETES MELLITUS, EXPERIMENTALdiseaseDIABETIC NEPHROPATHIESdiseasePROTEINURIAgeneNOX4geneAGTaction termexpressionaction termreactionaction termactivityixnAGT protein inhibits the reaction [Streptozocin results in increased activity of NOX4 protein]ixnStreptozocin plays a role in or acts as a marker for Diabetes Mellitus, ExperimentalixnAGT protein inhibits the reaction [Streptozocin results in increased expression of NOX4 mRNA]ixnStreptozocin results in increased activity of NOX4 proteinixnStreptozocin results in increased expression of NOX4 mRNAixnStreptozocin plays a role in or acts as a marker for ProteinuriaixnStreptozocin plays a role in or acts as a marker for Diabetic NephropathiesixnAGT has a real or putative therapeutic role towards Diabetic NephropathiesixnAGT has a real or putative therapeutic role towards Proteinuria20021991title0Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression.abstract127OBJECTIVE: To evaluate common genetic variations for association with symptomatic improvement in bipolar I depression following treatment with olanzapine/fluoxetine combination (OFC) or lamotrigine.
METHOD: Symptom improvement was assessed in 88 OFC-treated and 85 lamotrigine-treated white patients with bipolar I depression in the 7-week acute period of a randomized, double-blind study comparing OFC (6/25, 6/50, 12/25, or 12/50 mg/d [olanzapine/fluoxetine]) with lamotrigine (titrated to 200 mg/d). The original study was conducted from November 2003 to August 2004. Single nucleotide polymorphisms (SNPs) were genotyped in a set of 19 candidate genes corresponding to known sites of activity for olanzapine and fluoxetine or previously associated with antidepressant or antipsychotic response. Primary outcome was the reduction in Montgomery-Asberg Depression Rating Scale (MADRS) total score as assessed by the difference by genotype from baseline to week 7 from a mixed-effects repeated measures analysis with terms for visit, genotype, genotype-by-visit interaction, and baseline MADRS score as a covariate.
RESULTS: SNPs within the dopamine D(3) receptor and histamine H(1) receptor (HRH1) genes were significantly associated with response to OFC. SNPs within the dopamine D(2) receptor, HRH1, dopamine beta-hydroxylase, glucocorticoid receptor, and melanocortin 2 receptor genes were significantly associated with response to lamotrigine.
CONCLUSIONS: SNPs in specific candidate genes were associated with symptomatic improvement in a treatment-specific fashion. These results suggest the importance of dopaminergic effects in the treatment of patients with bipolar I depression and the potential utility of genotyping in selection of pharmacologic treatments for bipolar depression.chemLAMOTRIGINEchemFLUOXETINEchemOLANZAPINEdiseaseBIPOLAR DISORDERgeneHRH1geneDBHgeneMC2RgeneDRD2geneDRD3geneNR3C1action termcotreatmentaction termresponse to substanceixnlamotrigine has a real or putative therapeutic role towards Bipolar DisorderixnFluoxetine has a real or putative therapeutic role towards Bipolar Disorderixnolanzapine has a real or putative therapeutic role towards Bipolar DisorderixnDRD3 protein results in increased susceptibility to [olanzapine co-treated with Fluoxetine]ixnHRH1 protein results in increased susceptibility to [olanzapine co-treated with Fluoxetine]ixnDRD2 protein results in increased susceptibility to lamotrigineixnHRH1 protein results in increased susceptibility to lamotrigineixnDBH protein results in increased susceptibility to lamotrigineixnNR3C1 protein results in increased susceptibility to lamotrigineixnMC2R protein results in increased susceptibility to lamotrigine18395914title0Effect of Oxymatrine on the TGFbeta-Smad signaling pathway in rats with CCl4-induced hepatic fibrosis.abstract103AIM: To explore the anti-fibrotic effect of Oxymatrine on CCl4-induced liver fibrosis in rats and its modulation on the TGFbeta-Smad signaling pathway.
METHODS: One hundred healthy male SD rats were randomly divided into three groups: normal group (n = 20), treatment group of Oxymatrine (n = 40) and CCl4-induced fibrosis group (n = 40). Experimental hepatic fibrosis was induced by subcutaneous injection of carbon tetrachloride (CCl4 soluted in liquid paraffin with the concentration of 300 g/L, the dosage of injection was 3 mL/kg, twice per week for 8 wk). The treated rats received Oxymatrine via celiac injection at a dosage of 10 mg/kg twice a week at the same time. The deposition of collagen was observed with H&E and Masson staining. The concentration of serum TGF-beta1 was assayed with ELISA. The gene expression of Smads and CBP (CREB binding protein) was detected with in situ hybridization (ISH) and immunohistochemistry (IH), respectively. All the experimental figures were scanned and analyzed with special figure-analysis software.
RESULTS: A significant reduction of collagen deposition and rearrangement of the parenchyma was noted in the liver tissue of Oxymatrine-treated rats. The semiquantitative histological scores (2.43 +/- 0.47 microm2 vs 3.76 +/- 0.68 microm2, P < 0.05) and average area of collagen in those rats were significantly decreased when compared with hepatic cirrhosis model rats (94.41 +/- 37.26 microm2 vs 290.86 +/- 89.37 microm2, P < 0.05). The gene expression of Smad 3 mRNA was considerably decreased in the treated animals. The A value of Smad 3 mRNA was lower in the treated rats than the model rats (0.034 +/- 0.090 vs 0.167 +/- 0.092, P < 0.05). Contrarily, the A value of Smad 7 mRNA was increased considerably in the treated animals (0.175 +/- 0.065 vs 0.074 +/- 0.012, P < 0.05). There was an obvious decrease in the expression of CBP mRNA in treated rats as illuminated by a reduction of its A value when compared with model rats (0.065 +/- 0.049 vs 0.235 +/- 0.025, P < 0.001).
CONCLUSION: Oxymatrine is effective in reducing the production and deposition of collagen in the liver tissue of experimental rats. Oxymatrine could promote the expression of Smad 7 and inhibit the expression of Smad 3 and CBP in CCl4-induced hepatic fibrosis in SD rats, could modulate the fibrogenic signal transduction of TGFbeta-Smad pathway.chemCARBON TETRACHLORIDEchemOXYMATRINEdiseaseLIVER CIRRHOSIS, EXPERIMENTALgeneTGFB1geneCREBBPgeneSMAD3geneSMAD7action termreactionaction termexpressionixnoxymatrine inhibits the reaction [Carbon Tetrachloride results in increased expression of TGFB1 protein]ixnoxymatrine inhibits the reaction [Carbon Tetrachloride results in increased expression of SMAD3 mRNA]ixnoxymatrine inhibits the reaction [Carbon Tetrachloride results in increased expression of CREBBP mRNA]ixnoxymatrine has a real or putative therapeutic role towards Liver Cirrhosis, ExperimentalixnCarbon Tetrachloride plays a role in or acts as a marker for Liver Cirrhosis, ExperimentalixnCarbon Tetrachloride results in increased expression of TGFB1 proteinixnCarbon Tetrachloride results in increased expression of SMAD3 mRNAixnCarbon Tetrachloride results in increased expression of CREBBP mRNAixnoxymatrine results in increased expression of SMAD7 mRNA10803761title0Caffeine augments proteinuria in puromycin-aminonucleoside nephrotic rats.abstract75Several studies indicate that increased intrarenal adenosine concentrations may attenuate puromycin-aminonucleoside (PAN)-induced nephropathy in rats. The purpose of this study was to investigate the chronic effects of caffeine, a nonselective adenosine receptor antagonist, on renal function and structure in PAN-induced nephropathy. Animals were randomized to receive drinking water or 0.1% caffeine solution. PAN was administered in two doses to a subset from each group at 1 week (100 mg/kg, s.c.; Purom-1) and 15 wks (80 mg/kg, s.c.; Purom-2) after initiating caffeine treatment (PAN and CAFF-PAN groups). The remaining animals served as time controls (CON and CAFF groups). Renal excretory function was followed for 23 wks. Caffeine consumption significantly augmented PAN-induced proteinuria after both PAN injections (Purom-1 and Purom-2, p<0.05 and p<0.001 respectively; CAFF-PAN vs. PAN). In addition, caffeine potentiated the transient reduction in creatinine clearance (CrCl) induced by PAN. Caffeine consumption for 23 wks significantly reduced CrCl in conscious nephrotic animals (4.76 +/- 0.98 vs. 8.51 +/- 1.55 L/kg/day, CAFF-PAN vs. PAN). Seven days after both PAN injections, increased plasma renin activity was detected in animals that were consuming caffeine as compared with corresponding control groups (CAFF and CAFF + PAN vs CON and PAN, respectively). Eight weeks after the second injection of PAN, acute measures of renal hemodynamic and excretory function were compared in anesthetized animals and renal samples were analyzed for histological changes. In PAN-rats, caffeine treatment for 23 weeks significantly reduced inulin clearance (0.28 +/- 0.09 vs. 0.57 +/- 0.12 mL/min/gr kidney. CAFF-PAN vs PAN, p<0.05), tended to increase renal vascular resistance (59.0 +/- 9.5 vs. 42.9 +/- 5.5 mmHg/mL/min/gr kidney, CAFF-PAN vs. PAN, p < 0.06), potentiated the development of more severe tubulointerstitial damage (tubular atrophy, presence of proteinaceous material, tubular dilatation, interstitial inflammation, interstitial fibrosis), and tended to increase glomerulosclerosis. In conclusion, this study indicates that caffeine adversely affects renal function in PAN-nephrotic rats, and that this effect may be due, in part, to increased activity of the renin angiotensin system.chemPUROMYCIN AMINONUCLEOSIDEchemCAFFEINEdiseaseKIDNEY TUBULAR NECROSIS, ACUTEdiseaseGLOMERULOSCLEROSIS, FOCAL SEGMENTALdiseasePROTEINURIAdiseaseNEPHRITIS, INTERSTITIALgeneRENaction termsecretionixnPuromycin Aminonucleoside plays a role in or acts as a marker for ProteinuriaixnCaffeine plays a role in or acts as a marker for ProteinuriaixnCaffeine results in increased secretion of REN proteinixnCaffeine plays a role in or acts as a marker for Kidney Tubular Necrosis, AcuteixnCaffeine plays a role in or acts as a marker for Nephritis, InterstitialixnCaffeine plays a role in or acts as a marker for Glomerulosclerosis, Focal SegmentalixnPuromycin Aminonucleoside plays a role in or acts as a marker for Kidney Tubular Necrosis, AcuteixnPuromycin Aminonucleoside plays a role in or acts as a marker for Nephritis, InterstitialixnPuromycin Aminonucleoside plays a role in or acts as a marker for Glomerulosclerosis, Focal Segmental20082611title0Effects of spironolactone on atrial structural remodelling in a canine model of atrial fibrillation produced by prolonged atrial pacing.abstract137BACKGROUND AND PURPOSE: Suppression of the renin-angiotensin-aldosterone system can prevent atrial fibrillation (AF) by attenuating atrial structural remodelling but the role of aldosterone in AF prevention has not been investigated thoroughly. We explored whether the aldosterone antagonist, spironolactone, could improve atrial structural remodelling in long-term rapid pacing-induced AF.
EXPERIMENTAL APPROACH: Three groups of dogs were used, sham-operated, control and spironolactone-treated groups. Dogs in the control and spironolactone groups had right atrial pacing for 6 weeks. The spironolactone group was given spironolactone 1 week before and during the atrial pacing. After 6 weeks of pacing, atrial structural and functional changes were assessed by echocardiography, haemodynamic parameters by cardiac catheterization, histopathological changes by light and electron microscopy and cardiomyocyte apoptosis by TUNEL. Caspase-3, Bcl-2, bax, calpain I, calpastatin, matrix metalloproteinase (MMP)-9 and tissue inhibitors of metalloproteinase (TIMP)-1 were analysed by immunohistochemistry and Western blotting. The inducibility and duration of AF were measured by atrial burst pacing.
KEY RESULTS: After atrial pacing, the proportion of TUNEL positive cells, myolysis, atrial fibrosis and dilatation were all significantly increased and these changes were inhibited by spironolactone. Spironolactone treatment reversed the increased expression of caspase-3, bax, calpain I and MMP-9 and the decreased level of Bcl-2, calpastatin and TIMP-1, induced by chronic atrial pacing. Also spironolactone prevented the increased inducibility and duration of AF, induced by tachypacing.
CONCLUSIONS AND IMPLICATIONS: Treatment with spironolactone prevented myocardial apoptosis, myolysis, atrial fibrosis and dilatation, suggesting a possible beneficial effect of aldosterone antagonism on atrial structural remodelling in AF.chemSPIRONOLACTONEdiseaseATRIAL FIBRILLATIONgeneBAXgeneCAPN1geneBCL2geneMMP9geneCASTgeneTIMP1geneCASP3action termexpressionixnSpironolactone results in decreased expression of CASP3 proteinixnSpironolactone results in decreased expression of CAPN1 proteinixnSpironolactone results in decreased expression of MMP9 proteinixnSpironolactone results in increased expression of BCL2 proteinixnSpironolactone results in increased expression of CAST proteinixnSpironolactone results in increased expression of TIMP1 proteinixnSpironolactone results in decreased expression of BAX proteinixnSpironolactone has a real or putative therapeutic role towards Atrial Fibrillation19450571title0Panaxydol inhibits the proliferation and induces the differentiation of human hepatocarcinoma cell line HepG2.abstract111Panaxydol, a polyacetylene compound isolated from Panax ginseng, exerts anti-proliferative effects against malignant cells. No previous study, however, has been reported on its effects on hepatocellular carcinoma cells. Here, we investigated the effects of panaxydol on the proliferation and differentiation of human hepatocarcinoma cell line HepG2. We studied by electronic microscopy of morphological and ultrastructural changes induced by panaxydol. We also examined the cytotoxicities of panaxydol against HepG2 cells using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide assay and the effect of panaxydol on cell cycle distributions by flow cytometry. We investigated the production of liver proteins in panaxydol-treated cells including alpha-fetoprotein and albumin and measured the specific activity of alkaline phosphatase and gamma-glutamyl transferase. We further investigated the effects of panaxydol on the expression of Id-1, Id-2, p21 and pRb by RT-PCR or immunoblotting analysis. We found that panaxydol inhibited the proliferation of HepG2 cells and caused morphological and ultrastructural changes in HepG2 cells resembling more mature forms of hepatocytes. Moreover, panaxydol induced a cell cycle arrest at the G(1) to S transition in HepG2 cells. It also significantly decreased the secretion of alpha-fetoprotein and the activity of gamma-glutamyl transferase. By contrast, panaxydol remarkably increased the secretion of albumin and the alkaline phosphatase activity. Furthermore, panaxydol increased the mRNA content of p21 while reducing that of Id-1 and Id-2. Panaxydol also increased the protein levels of p21, pRb and the hypophosphorylated pRb in a dose-dependent manner. These findings suggest that panaxydol is of value for further exploration as a potential anti-cancer agent.chemPANAXYDOLdiseaseCARCINOMA, HEPATOCELLULARgeneALBgeneID2geneID1geneRB1geneAFPgeneCDKN1Aaction termexpressionaction termsecretionixnpanaxydol has a real or putative therapeutic role towards Carcinoma, Hepatocellularixnpanaxydol results in decreased secretion of AFP proteinixnpanaxydol results in increased secretion of ALB proteinixnpanaxydol results in increased expression of CDKN1A mRNAixnpanaxydol results in decreased expression of ID1 mRNAixnpanaxydol results in decreased expression of ID2 mRNAixnpanaxydol results in increased expression of CDKN1A proteinixnpanaxydol results in increased expression of RB1 proteinixnpanaxydol results in increased expression of RB1 protein modified form10721769title0Arsenic-induced apoptosis in malignant cells in vitro.abstract55Arsenic trioxide-induced apoptosis was identified by morphological change and nucleosomal DNA fragmentation in hematopoietic malignant cells and neuroblastoma cells. Arsenic trioxide directly induced apoptosis in the acute promyelocytic cell line NB4 cells at a low dose of 1 microM, whereas all-trans-retinoic acid caused the cells to differentiate and finally induced apoptosis. In addition to the involvement of caspase 3 in arsenic trioxide-induced apoptosis of NB4 cells, the activation of caspase 8 was also shown to be involved by Western blot analysis or by apoptosis inhibition assay using caspase 8 inhibitor Ac-IETD-CHO. The down-regulation of Bcl-2 protein was shown in arsenic trioxide-treated pre-apoptotic and early apoptotic mouse B-cell line LyH7 cells, which overexpress Bcl-2 protein, by the studies of Western blot and immunoelectron microscopy. Arsenic trioxide also induced apoptosis in the majority of neuroblastomas cell lines. The arsenic-induced apoptosis in neuroblastoma cell lines was mediated by the activation of caspase 3 in all cases tested. In regard to the intracellular content of reduced glutathione in various neuroblastoma cell lines, the level in the cells sensitive to arsenic trioxide was under 40 nmol/mg protein, but the cells having more than 40 nmol/mg protein did not undergo apoptosis. N-acetylcysteine protected neuroblastoma cells from arsenic-induced apoptosis. Therefore, the intracellular glutathione content may be a good indicator of application of arsenic trioxide for various kinds of cancer cells. Our results raise the possibility that arsenic trioxide will be effective even against a solid tumor such as neuroblastoma and warrants clinical trials for patients with other kinds of tumors not only by systemic therapy but also using local therapy.chemACETYLCYSTEINEchemACETYL-ISOLEUCYL-GLUTAMYL-THREONYL-ASPARTYL-ALDEHYDEchemTRETINOINchemARSENIC TRIOXIDEdiseaseNEUROBLASTOMAgeneBCL2geneCASP8geneCASP3action termexpressionaction termactivityixnarsenic trioxide results in increased activity of CASP8 proteinixnarsenic trioxide results in decreased expression of BCL2 proteinixnarsenic trioxide results in increased activity of CASP3 proteinixnarsenic trioxide has a real or putative therapeutic role towards Neuroblastoma16565415title0Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity.abstract90VEGF or VEGF-A is a major regulator of angiogenesis and has been recently shown to be important in organ repair. The potential role of VEGF in acetaminophen (APAP)-induced hepatotoxicity and recovery was investigated in B6C3F1 male mice. Mice were treated with APAP (300 mg/kg ip) and killed at various time points that reflect both the acute and recovery stages of toxicity. VEGF-A protein levels were increased 7-fold at 8 h and followed the development of hepatotoxicity. VEGF receptor 1, 2, and 3 (VEGFR1, VEGFR2, and VEGFR3, respectively) expression increased throughout the time course, with maximal expression at 48, 8, and 72 h, respectively. Treatment with the VEGF receptor inhibitor SU5416 (25 mg/kg ip at 3 h) had no effect on toxicity at 6 or 24 h. In further studies, the role of SU5416 on the late stages of toxicity was examined. Treatment of mice with APAP and SU5416 (25 mg/kg ip at 3 h) resulted in decreased expression of PCNA, a marker of cellular proliferation. Expression of platelet endothelial cell adhesion molecule, a measure of small vessel density, and endothelial nitric oxide synthase (NOS), a downstream target of VEGFR2, were increased at 48 and 72 h following toxic doses of APAP, and treatment with SU5416 decreased their expression. These data indicate that endogenous VEGF is critically important to the process of hepatocyte regeneration in APAP-induced hepatotoxicity in the mouse.chemSEMAXINIBchemACETAMINOPHENdiseaseDRUG-INDUCED LIVER INJURYgenePCNAgeneKDRgenePECAM1geneVEGFAgeneNOS3geneFLT1geneFLT4action termreactionaction termexpressionaction termcotreatmentixnAcetaminophen results in increased expression of FLT4 proteinixn[Acetaminophen co-treated with Semaxinib] results in decreased expression of PCNA proteinixnAcetaminophen results in increased expression of NOS3 proteinixnAcetaminophen results in increased expression of PECAM1 proteinixnAcetaminophen plays a role in or acts as a marker for Drug-Induced Liver InjuryixnAcetaminophen results in increased expression of KDR proteinixnAcetaminophen results in increased expression of VEGFA proteinixnAcetaminophen results in increased expression of FLT1 proteinixnSemaxinib inhibits the reaction [Acetaminophen results in increased expression of PECAM1 protein]ixnSemaxinib inhibits the reaction [Acetaminophen results in increased expression of NOS3 protein]18778786title0Realgar-induced differentiation is associated with MAPK pathways in HL-60 cells.abstract81The clinical efficacy and safety of realgar (arsenic sulfide, As(4)S(4)) in the treatment of acute promyelocytic leukemia in China have given rise to an upsurge in research on the underlying mechanism. We prepared realgar nanoparticles (RNPs) to examine their effect on the differentiation of HL-60 cells. Treatment with RNPs at 6 microM for 72 h induced cell differentiation that was assessed by morphological change, NBT reductive ability, and elevation of CD11b expression at both mRNA and protein levels. The RNP-induced differentiation was synergized, enhanced and suppressed by the inhibition of p38 MAPK, JNK and ERK pathways, respectively. Our findings demonstrate that MAPK signaling pathways are closely related to the RNP-induced differentiation in HL-60 cells.chemANTHRA(1,9-CD)PYRAZOL-6(2H)-ONEchem4-(4-FLUOROPHENYL)-2-(4-HYDROXYPHENYL)-5-(4-PYRIDYL)IMIDAZOLEchemARSENIC DISULFIDEchemPD 98059diseaseLEUKEMIA, PROMYELOCYTIC, ACUTEgeneITGAMaction termreactionaction termexpressionixnarsenic disulfide has a real or putative therapeutic role towards Leukemia, Promyelocytic, Acuteixnarsenic disulfide analog results in increased expression of ITGAM mRNAixnarsenic disulfide analog results in increased expression of ITGAM proteinixnPD 98059 inhibits the reaction [arsenic disulfide analog results in increased expression of ITGAM protein]ixnPD 98059 inhibits the reaction [arsenic disulfide analog results in increased expression of ITGAM mRNA]ixnanthra(1,9-cd)pyrazol-6(2H)-one promotes the reaction [arsenic disulfide analog results in increased expression of ITGAM protein]ixnanthra(1,9-cd)pyrazol-6(2H)-one promotes the reaction [arsenic disulfide analog results in increased expression of ITGAM mRNA]ixn4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole promotes the reaction [arsenic disulfide analog results in increased expression of ITGAM protein]ixn4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole promotes the reaction [arsenic disulfide analog results in increased expression of ITGAM mRNA]1867428title0Deliberate hypotension with nicardipine or nitroprusside during total hip arthroplasty.abstract88To induce deliberate hypotension during anesthesia, nicardipine was administered to patients undergoing total hip arthroplasty and was randomly compared with nitroprusside. Hemodynamic measurements were performed before and 10, 20, 30, and 60 min after starting to administer either nicardipine (n = 12) or nitroprusside (n = 12) (B, T1, T2, T3, and T4, respectively); at the end of drug infusion (T5); and 10, 20, and 60 min later (T6, T7, and T8, respectively). Plasma renin activity and catecholamine levels were measured at B, T1, T5, T6, and T7. In addition, plasma nicardipine concentration was measured in five patients at T1, T2, T5, T7, and T8. As with nitroprusside, nicardipine administration (1-3 micrograms.kg-1.min-1, after a titration dose of 4.7 +/- 1.5 mg) resulted in hypotension (up to -34% +/- 3%), a decrease in systemic vascular resistances (up to -49% +/- 4%), and increases in heart rate (up to +17% +/- 6%), cardiac index (up to +37% +/- 8%), plasma norepinephrine (up to +63% +/- 17%) and epinephrine (up to +232% +/- 68%) levels, and plasma renin activity (up to +336% +/- 207%). Ten and 20 minutes after discontinuation of the hypotensive drug, nicardipine led to persistent vasodilation and hypotension, which differed significantly from the hypertensive rebound observed after nitroprusside discontinuation, despite a similar increase in plasma renin activity and catecholamine levels. Our results indicate that after the infusion was terminated, the nicardipine-induced vasodilation was opposed to the vasoconstrictive effects of angiotensin II and catecholamines, thus avoiding hypertensive rebound.(ABSTRACT TRUNCATED AT 250 WORDS)chemNICARDIPINEchemNITROPRUSSIDEdiseaseHYPOTENSIONgeneRENaction termactivityixnNitroprusside plays a role in or acts as a marker for HypotensionixnNicardipine plays a role in or acts as a marker for HypotensionixnNicardipine results in increased activity of REN proteinixnNitroprusside results in increased activity of REN protein20724260title0Abrogating HSP response augments cell death induced by As2O3 in glioma cell lines.abstract83OBJECTIVES: We previously reported that Arsenic trioxide (ATO) can inhibit glioma growth both in vitro and in vivo. While the use of ATO alone for solid tumor treatment sometimes was found to be ineffective which may be due to the protective pathways including heat shock proteins (HSPs) response induced by ATO. In this study, we modified HSPs expression to investigate whether HSPs had some effect on ATO induced glioma cell death.
METHODS: Trypan bule exclusion assay, mitochondrial membrane potential (MMP) Assay, and SubG1 detection were used to evaluate cell viability and western-blot was employed to detect HSPs and some apoptosis markers expression induced by ATO. Heat pre-treatment, HSPs inhibitor, or Heat Shock factor-1 (HSF1) knockdown by SiRNA was employed to modify HSPs levels.
RESULTS: It was showed that KNK437 (HSPs inhibitor) or HSF1 knockdown significantly enhanced cell death, MMP disruption, JNK phosphorylation and caspase-3 cleavage induced by ATO, which was accompanied by abrogation of HSPs induction, while heat pre-treatment with clear HSPs induction had strong protection on the effects mentioned above.
CONCLUSION: Those data suggested that HSPs play protective roles on ATO induced cell death in glioma. Inhibition of HSPs may have a synergistic effect with ATO on glioma treatment.chemKNK 437chemARSENIC TRIOXIDEdiseaseGLIOMAgeneHSP70geneCASP3geneDNAJB1geneHSF1geneJNKaction termreactionaction termexpressionaction termphosphorylationaction termcleavageaction termresponse to substanceixnarsenic trioxide results in increased cleavage of CASP3 proteinixnarsenic trioxide has a real or putative therapeutic role towards Gliomaixnarsenic trioxide results in increased expression of DNAJB1 proteinixnKNK 437 inhibits the reaction [arsenic trioxide results in increased expression of HSP70 protein]ixnarsenic trioxide results in increased expression of HSP70 proteinixnarsenic trioxide results in increased phosphorylation of JNK proteinixnKNK 437 promotes the reaction [arsenic trioxide results in increased phosphorylation of JNK protein]ixnKNK 437 promotes the reaction [arsenic trioxide results in increased cleavage of CASP3 protein]ixnKNK 437 inhibits the reaction [arsenic trioxide results in increased expression of DNAJB1 protein]ixnHSF1 protein affects the susceptibility to arsenic trioxide18841091title0Regulation of alpha-synuclein expression by liver X receptor ligands in vitro.abstract79Alpha-synuclein is a lipid-binding protein expressed in neurons and oligodendrocytes which is increased in Parkinson''s disease. We identified two putative liver X receptor (LXR) response elements in the human alpha-synuclein gene and used synthetic (TO901317, GW3695) and physiological (27-hydroxycholesterol) LXR activators to assess regulation of alpha-synuclein. LXR ligands upregulated alpha-synuclein mRNA by two-five-fold in human SK-N-SH neurons and three-six-fold in human MO3.13 oligodendrocytes. Significant 50% to four-fold induction of alpha-synuclein protein was also detected. Under these conditions, mRNA for LXR-responsive gene ABCA1 was significantly upregulated 15-40-fold and 5-25-fold in neurons and oligodendrocytes, respectively. LXR may, therefore, contribute to the regulation of alpha-synuclein expression in neurons and oligodendrocytes.chemTO-901317chemGW 3965chem27-HYDROXYCHOLESTEROLdiseasePARKINSON DISEASEgeneSNCAgeneABCA1action termexpressionixnSNCA plays a role in or acts as a marker for Parkinson DiseaseixnTO-901317 results in increased expression of SNCA mRNAixnGW 3965 results in increased expression of SNCA mRNAixn27-hydroxycholesterol results in increased expression of SNCA mRNAixnTO-901317 results in increased expression of SNCA proteinixnGW 3965 results in increased expression of SNCA proteinixn27-hydroxycholesterol results in increased expression of SNCA proteinixnTO-901317 results in increased expression of ABCA1 mRNAixnGW 3965 results in increased expression of ABCA1 mRNAixn27-hydroxycholesterol results in increased expression of ABCA1 mRNA16014734title0Trans, trans-2,4-decadienal, a product found in cooking oil fumes, induces cell proliferation and cytokine production due to reactive oxygen species in human bronchial epithelial cells.abstract186Dienaldehydes are by-products of peroxidation of polyunsaturated lipids and commonly found in many foods or food-products. Both National Cancer Institute (NCI) and NTP have expressed great concern on the potential genotoxicity and carcinogenicity of dienaldehydes. Trans, trans-2,4-decadienal (tt-DDE or 2,4-De), a specific type of dienaldehyde, is abundant in heated oils and has been associated with lung adenocarcinoma development in women due to their exposure to oil fumes during cooking. Cultured human bronchial epithelial cells (BEAS-2B cells) were exposed to 0.1 or 1.0 microM tt-DDE for 45 days, and oxidative stress, reactive oxygen species (ROS) production, GSH/GSSG ratio, cell proliferation, and expression of TNFalpha and IL-1beta were measured. The results show that tt-DDE induced oxidative stress, an increase in ROS production, and a decrease in GSH/GSSG ratio (glutathione status) in a dose-dependent manner. Treatment of BEAS-2B cells with 1.0 microM tt-DDE for 45 days increased cell proliferation and the expression and release of pro-inflammatory cytokines TNFalpha and IL-1beta. Cotreatment of BEAS-2B cells with antioxidant N-acetylcysteine prevented tt-DDE-induced cell proliferation and release of cytokines. Therefore, these results suggest that tt-DDE-induced changes may be due to increased ROS production and enhanced oxidative stress. Since increased cell proliferation and the release of TNF-alpha and IL-1beta are believed to be involved in tumor promotion, our results suggest that tt-DDE may play a role in cancer promotion. Previous studies on dienaldehydes have focused on their genotoxic or carcinogenic effects in the gastrointestinal tract; the present study suggests a potential new role of tt-DDE as a tumor promoter in human lung epithelial cells.chem2-TRANS-4-TRANS-DECADIENALchemACETYLCYSTEINEdiseaseLUNG NEOPLASMSdiseaseADENOCARCINOMAgeneTNFgeneIL1Baction termexpressionaction termreactionaction termsecretionixnAcetylcysteine inhibits the reaction [2-trans-4-trans-decadienal results in increased expression of and results in increased secretion of TNF protein]ixn2-trans-4-trans-decadienal plays a role in or acts as a marker for Lung Neoplasmsixn2-trans-4-trans-decadienal results in increased expression of and results in increased secretion of TNF proteinixn2-trans-4-trans-decadienal plays a role in or acts as a marker for Adenocarcinomaixn2-trans-4-trans-decadienal results in increased expression of and results in increased secretion of IL1B proteinixnAcetylcysteine inhibits the reaction [2-trans-4-trans-decadienal results in increased expression of and results in increased secretion of IL1B protein]11243714title0Tephrosia purpurea alleviates phorbol ester-induced tumor promotion response in murine skin.abstract93In recent years, considerable emphasis has been placed on identifying new cancer chemopreventive agents, which could be useful for the human population. Tephrosia purpurea has been shown to possess significant activity against hepatotoxicity, pharmacological and physiological disorders. Earlier we showed that Tephrosia purpurea inhibits benzoyl peroxide-mediated cutaneous oxidative stress and toxicity. In the present study, we therefore assessed the effect of Tephrosia purpurea on 12-O-tetradecanoyl phorbal-13-acetate (TPA; a well-known phorbol ester) induced cutaneous oxidative stress and toxicity in murine skin. The pre-treatment of Swiss albino mice with Tephrosia purpurea prior to application of croton oil (phorbol ester) resulted in a dose-dependent inhibition of cutaneous carcinogenesis. Skin tumor initiation was achieved by a single topical application of 7,12-dimethyl benz(a)anthracene (DMBA) (25 microg per animal per 0.2 ml acetone) to mice. Ten days later tumor promotion was started by twice weekly topical application of croton oil (0.5% per animal per 0.2 ml acetone, v /v). Topical application of Tephrosia purpurea 1 h prior to each application of croton oil (phorbol ester) resulted in a significant protection against cutaneous carcinogenesis in a dose-dependent manner. The animals pre-treated with Tephrosia purpurea showed a decrease in both tumor incidence and tumor yield as compared to the croton oil (phorbol ester)-treated control group. In addition, a significant reduction in TPA-mediated induction in cutaneous ornithine decarboxylase (ODC) activity and [3H]thymidine incorporation was also observed in animals pre-treated with a topical application of Tephrosia purpurea. The effect of topical application of Tephrosia purpurea on TPA-mediated depletion in the level of enzymatic and non-enzymatic molecules in skin was also evaluated and it was observed that topical application of Tephrosia purpurea prior to TPA resulted in the significant recovery of TPA-mediated depletion in the level of these molecules, namely glutathione, glutathione S-transferase, glutathione reductase and catalase. From these data we suggest that Tephrosia purpurea can abrogate the tumor-promoting effect of croton oil (phorbol ester) in murine skin.chemCROTON OILchemPLANT EXTRACTSchemTETRADECANOYLPHORBOL ACETATEdiseaseSKIN NEOPLASMSgeneODC1geneCATgeneGSRaction termreactionaction termactivityixnTetradecanoylphorbol Acetate plays a role in or acts as a marker for Skin NeoplasmsixnCroton Oil plays a role in or acts as a marker for Skin NeoplasmsixnPlant Extracts has a real or putative therapeutic role towards Skin NeoplasmsixnTetradecanoylphorbol Acetate results in increased activity of ODC1 proteinixnCroton Oil inhibits the reaction [Tetradecanoylphorbol Acetate results in increased activity of ODC1 protein]ixnTetradecanoylphorbol Acetate results in decreased activity of GSR proteinixnTetradecanoylphorbol Acetate results in decreased activity of CAT proteinixnCroton Oil inhibits the reaction [Tetradecanoylphorbol Acetate results in decreased activity of GSR protein]ixnCroton Oil inhibits the reaction [Tetradecanoylphorbol Acetate results in decreased activity of CAT protein]14586741title0Roles of connective tissue growth factor and prostanoids in early streptozotocin-induced diabetic rat kidney: the effect of aspirin treatment.abstract143BACKGROUND: Connective tissue growth factor (CTGF) is a cysteine-rich growth factor induced by transforming growth factor-beta (TGF-beta) and is thought to play a critical role in TGF-beta-stimulated extracellular matrix accumulation. To explore its involvement in early diabetic nephropathy, we investigated the time course of CTGF gene expression and its regulation in streptozotocin (STZ)-induced diabetic rat kidney.
METHODS: Northern blot analysis for CTGF, TGF-beta, and fibronectin expression was performed in the glomeruli of STZ-induced diabetic rats from 3 days to 12 weeks after the induction of diabetes, together with histological examination. To investigate the role of prostanoids in this process, aspirin was administered in one group of diabetic rats. Furthermore, CTGF expression was analyzed in rat mesangial cells cultured under high-glucose conditions.
RESULTS: Glomerular expression of CTGF and TGF-beta1 mRNA was coordinately upregulated as early as day 3, followed by fibronectin induction and mesangial matrix accumulation. Chronic aspirin treatment in diabetic rats significantly attenuated mesangial expansion, and effectively suppressed CTGF induction, as well as inhibiting the upregulation of TGF-beta1 and fibronectin expression. In cultured mesangial cells, aspirin treatment abolished high glucose-stimulated CTGF upregulation.
CONCLUSIONS: These results indicate that CTGF expressed in the glomeruli is upregulated in the early stage of STZ-induced diabetic nephropathy in rats, and could be a critical mediator of the development of diabetic glomerulosclerosis. In addition, the modulatory effects of aspirin during this process suggest a role of the cyclooxygenase pathway in the progression of diabetic nephropathy.chemSTREPTOZOCINchemASPIRINchemGLUCOSEdiseaseDIABETES MELLITUS, EXPERIMENTALgeneTGFB1geneCTGFgeneFN1action termexpressionaction termreactionixnAspirin inhibits the reaction [Streptozocin results in increased expression of CTGF mRNA]ixnStreptozocin results in increased expression of CTGF mRNAixnStreptozocin plays a role in or acts as a marker for Diabetes Mellitus, ExperimentalixnAspirin inhibits the reaction [Streptozocin results in increased expression of TGFB1 mRNA]ixnStreptozocin results in increased expression of TGFB1 mRNAixnStreptozocin results in increased expression of FN1ixnAspirin inhibits the reaction [Streptozocin results in increased expression of FN1]ixnGlucose results in increased expression of CTGF mRNAixnAspirin inhibits the reaction [Glucose results in increased expression of CTGF mRNA]19654922title0The adjuvant effect of ambient particulate matter is closely reflected by the particulate oxidant potential.abstract109BACKGROUND: It has been demonstrated that ambient particulate matter (PM) can act as an adjuvant for allergic sensitization. Redox-active organic chemicals on the particle surface play an important role in PM adverse health effects and may determine the adjuvant effect of different particle types according to their potential to perturb redox equilibrium in the immune system.
OBJECTIVES: We determined whether the adjuvant effect of ambient fine particles versus ultrafine particles (UFPs) is correlated to their prooxidant potential.
METHODS: We have established an intranasal sensitization model that uses ambient PM as a potential adjuvant for sensitization to ovalbumin (OVA), which enhances the capacity for secondary OVA challenge to induce allergic airway inflammation.
RESULTS: UFPs with a greater polycyclic aromatic hydrocarbon (PAH) content and higher oxidant potential enhanced OVA sensitization more readily than did fine particles. This manifests as enhanced allergic inflammation upon secondary OVA challenge, leading to eosinophilic inflammation and mucoid hyperplasia starting at the nasal turbinates all the way down to the small pulmonary airways. The thiol antioxidant N-acetyl cysteine was able to suppress some of these sensitization events.
CONCLUSIONS: The adjuvant effects of ambient UFP is determined by their oxidant potential, which likely plays a role in changing the redox equilibrium in the mucosal immune system.chemPOLYCYCLIC HYDROCARBONS, AROMATICchemPARTICULATE MATTERchemACETYLCYSTEINEdiseaseHYPERSENSITIVITYgeneIL6geneCCL3geneIL5geneCXCL1geneTNFgeneCCL2geneIL13action termexpressionaction termcotreatmentixnPolycyclic Hydrocarbons, Aromatic plays a role in or acts as a marker for HypersensitivityixnAcetylcysteine has a real or putative therapeutic role towards Hypersensitivityixn[Polycyclic Hydrocarbons, Aromatic co-treated with Particulate Matter] results in increased expression of IL5 proteinixn[Polycyclic Hydrocarbons, Aromatic co-treated with Particulate Matter] results in increased expression of CCL2 proteinixnParticulate Matter plays a role in or acts as a marker for Hypersensitivityixn[Polycyclic Hydrocarbons, Aromatic co-treated with Particulate Matter] results in increased expression of CXCL1 proteinixn[Polycyclic Hydrocarbons, Aromatic co-treated with Particulate Matter] results in increased expression of IL13 proteinixn[Polycyclic Hydrocarbons, Aromatic co-treated with Particulate Matter] results in increased expression of CCL3 proteinixn[Polycyclic Hydrocarbons, Aromatic co-treated with Particulate Matter] results in increased expression of IL6 proteinixn[Polycyclic Hydrocarbons, Aromatic co-treated with Particulate Matter] results in increased expression of TNF protein11701772title0Oxidative impairment in scrapie-infected mice is associated with brain metals perturbations and altered antioxidant activities.abstract128Prion diseases are characterized by the conversion of the normal cellular prion protein (PrP(C)) into a pathogenic isoform (PrP(Sc)). PrP(C) binds copper, has superoxide dismutase (SOD)-like activity in vitro, and its expression aids in the cellular response to oxidative stress. However, the interplay between PrPs (PrP(C), PrP(Sc) and possibly other abnormal species), copper, anti-oxidation activity and pathogenesis of prion diseases remain unclear. In this study, we reported dramatic depression of SOD-like activity by the affinity-purified PrPs from scrapie-infected brains, and together with significant reduction of Cu/Zn-SOD activity, correlates with significant perturbations in the divalent metals contents. We also detected elevated levels of nitric oxide and superoxide in the infected brains, which could be escalating the oxidative modification of cellular proteins, reducing gluathione peroxidase activity and increasing the levels of lipid peroxidation markers. Taken together, our results suggest that brain metal imbalances, especially copper, in scrapie infection is likely to affect the anti-oxidation functions of PrP and SODs, which, together with other cellular dysfunctions, predispose the brains to oxidative impairment and eventual degeneration. To our knowledge, this is the first study documenting a physiological connection between brain metals imbalances, the anti-oxidation function of PrP, and aberrations in the cellular responses to oxidative stress, in scrapie infection.chemNITRIC OXIDEchemMANGANESEchemCALCIUMchemZINCchemCOPPERchemSUPEROXIDESdiseasePRION DISEASESdiseaseSCRAPIEgeneSOD1genePRNPixnManganese plays a role in or acts as a marker for ScrapieixnCalcium plays a role in or acts as a marker for ScrapieixnPRNP plays a role in or acts as a marker for Prion DiseasesixnPRNP plays a role in or acts as a marker for ScrapieixnSOD1 plays a role in or acts as a marker for ScrapieixnSuperoxides plays a role in or acts as a marker for ScrapieixnNitric Oxide plays a role in or acts as a marker for ScrapieixnCopper plays a role in or acts as a marker for ScrapieixnZinc plays a role in or acts as a marker for Scrapie20046642title0Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats.abstract172Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum tumor necrosis factor-alpha (TNFalpha), hippocampal MT and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition.chemCARMUSTINEchemZINC SULFATEdiseaseLEARNING DISORDERSdiseaseMEMORY DISORDERSdiseaseCOGNITION DISORDERSgeneGSRgeneTNFgeneCASP3action termreactionaction termexpressionaction termactivityixnCarmustine results in increased activity of CASP3 proteinixnCarmustine plays a role in or acts as a marker for Memory DisordersixnZinc Sulfate inhibits the reaction [Carmustine results in increased activity of CASP3 protein]ixnCarmustine plays a role in or acts as a marker for Learning DisordersixnCarmustine results in decreased activity of GSR proteinixnCarmustine results in increased expression of TNF proteinixnZinc Sulfate inhibits the reaction [Carmustine results in decreased activity of GSR protein]ixnZinc Sulfate inhibits the reaction [Carmustine results in increased expression of TNF protein]ixnCarmustine plays a role in or acts as a marker for Cognition DisordersixnZinc Sulfate has a real or putative therapeutic role towards Cognition Disorders8396608title0Comparison of CD271 (adapalene) and all-trans retinoic acid in human skin: dissociation of epidermal effects and CRABP-II mRNA expression.abstract139A new synthetic retinoid analogue, adapalene (6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, CD271), which is relatively selective for retinoic acid receptor beta, was noted to be an effective comedolytic agent in the rhino mouse model and to have clinical efficacy against acne. In pursuit of this observation, we studied the effects of CD271 on the development of erythema, spongiosis, and epidermal hyperplasia as well as other well-characterized markers of in vivo retinoid action after 4 d of occluded topical treatment. The objective of the study was to elucidate further those parameters associated with potential clinical efficacy. Twenty-five subjects were treated with 0.1% all-trans retinoic acid cream, all-trans retinoic acid vehicle, 0.1% CD271 gel, or CD271 vehicle under occlusion for 4 d. Only all-trans retinoic acid induced erythema (p < 0.01 versus all other treatments). Similarly, histologic analysis revealed that epidermal hyperplasia and spongiosis were induced only by all-trans retinoic acid (p < 0.01 versus all other treatments). By immunohistochemical analysis: all-trans retinoic acid increased expression of epidermal transglutaminase, involucrin, and calgranulin (p < 0.05 versus all other treatments). In contrast to these data, both CD271 and all-trans retinoic acid caused marked and significant (p < 0.05) elevation of cellular retinoic acid-binding protein-II (CRABP-II) messenger ribonucleic acid steady-state levels as judged by quantitative RNA blot analysis. Although CD271 treatment did not lead to erythema or affect epidermal morphology, its ability to induce a marker of retinoid action (i.e., CRABP-II) was 70% the potency of all-trans retinoic acid. This study suggests that CRABP-II gene expression may be a more sensitive indicator of retinoid biologic activity in skin than are erythema or changes in epidermal morphology and differentiation.chemTRETINOINchemADAPALENEdiseaseERYTHEMAdiseaseACNE VULGARISdiseaseHYPERPLASIAdiseaseEDEMAgeneIVLgeneTGM1geneCRABP2geneRARBaction termexpressionaction termbindingixnadapalene has a real or putative therapeutic role towards Acne Vulgarisixnadapalene binds to RARB proteinixnTretinoin plays a role in or acts as a marker for ErythemaixnTretinoin plays a role in or acts as a marker for HyperplasiaixnTretinoin plays a role in or acts as a marker for EdemaixnTretinoin results in increased expression of TGM1 proteinixnTretinoin results in increased expression of IVL proteinixnTretinoin results in increased expression of CRABP2 mRNAixnadapalene results in increased expression of CRABP2 mRNA7582491title0Cytokine-mediated inflammatory hyperalgesia limited by interleukin-10.abstract711. The effect of interleukin-10 (IL-10) upon the hyperalgesic activities in rats of bradykinin, tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E2 (PGE2) and carrageenin were investigated in a model of mechanical hyperalgesia. 2. Hyperalgesic responses to bradykinin (1 micrograms) were inhibited in a dose-dependent manner by prior treatment with IL-10 (1-100 ng). 3. Hyperalgesic responses to TNF alpha (2.5 pg), IL-1 beta (0.5 pg) and IL-6 (1.0 ng) but not to IL-8 (0.1 ng) and PGE2 (50 ng and 100 ng) were inhibited by prior treatment with IL-10 (10 ng). 4. Hyperalgesic responses to carrageenin (100 micrograms) were inhibited by IL-10 (10 ng) when this cytokine was injected before but not after the carrageenin. 5. A monoclonal antibody to mouse IL-10 potentiated the hyperalgesic responses to carrageenin (10 micrograms) and TNF alpha (0.025 pg) but not that to IL-8 (0.01 ng). 6. In in vitro experiments in human peripheral blood mononuclear cells (MNCs), IL-10 (0.25-4.0 ng ml-1) inhibited in a dose-dependent manner PGE2 production by MNCs stimulated with IL-1 beta (1-64 ng ml-1) or endotoxin (lipopolysaccharide, LPS, 1 iu = 143 pg ml-1) but evoked only small increases in IL-1ra production. 7. These data suggest that IL-10 limits the inflammatory hyperalgesia evoked by carrageenin and bradykinin by two mechanisms: inhibition of cytokine production and inhibition of IL-1 beta evoked PGE2 production. Our data suggest that the latter effect is not mediated via IL-10 induced IL-Ira and may result from suppression by IL-10 of prostaglandin H synthase-2 (COX-2).chemENDOTOXINSchemDINOPROSTONEchemCARRAGEENANchemBRADYKININdiseaseHYPERALGESIAgeneIL1BgeneIL6geneTNFgeneIL10action termreactionaction termabundanceixnIL1B plays a role in or acts as a marker for HyperalgesiaixnTNF plays a role in or acts as a marker for HyperalgesiaixnBradykinin plays a role in or acts as a marker for HyperalgesiaixnIL6 plays a role in or acts as a marker for HyperalgesiaixnCarrageenan plays a role in or acts as a marker for HyperalgesiaixnIL1B protein results in increased abundance of DinoprostoneixnIL10 protein inhibits the reaction [Endotoxins results in increased abundance of Dinoprostone]ixnIL10 has a real or putative therapeutic role towards HyperalgesiaixnIL10 protein inhibits the reaction [IL1B protein results in increased abundance of Dinoprostone]15135802title0In vitro effect of indomethacin and interferon-alpha on Th1 and Th2 cytokine synthesis in patients with chronic hepatitis C.abstract125Current evidences suggest that non-steroidal anti-inflammatory drugs could enhance the antiviral activity of interferon-alpha in chronic HCV infection. In this study, we investigated the effect of indomethacin, a non-steroidal anti-inflammatory drug, and interferon-alpha on cytokine production by peripheral blood mononuclear cells from 12 untreated patients with chronic hepatitis C. We evaluated the effect of incubation with indomethacin, interferon-alpha or both on synthesis of Th1- (interleukin-2, interferon-gamma) and Th2-associated cytokines (interleukin-4, interleukin-10), and of the antiviral protein 2'',5''-oligoadenylate synthetase. Interferon-alpha induced a significant increase in production of interleukin-2. Smaller increases were also seen in the presence of indomethacin, while incubation with both indomethacin and interferon-alpha leads to a synergistic effect. Incubation with indomethacin decreased both interleukin-4 and interleukin-10, whereas interferon-alpha increased these cytokines. The addition of indomethacin to interferon-alpha significantly reversed this interferon-induced increase. Finally, both indomethacin and the association interferon-alpha plus indomethacin determined a significant increase in 2'',5''-oligoadenylate synthetase production compared to both baseline and interferon-alpha alone. In conclusion, indomethacin was able to enhance the antiviral activity of interferon-alpha and to modulate the interferon-induced Th1 and Th2 cytokine response by increasing the Th1-response, fundamental for sustained clearance of HCV, and by decreasing the Th-2 type response, associated with HCV persistence.chemINTERFERON ALFA-N1chemINDOMETHACINdiseaseHEPATITIS C, CHRONICgeneIL10geneIL2geneIL4action termreactionaction termsecretionixnIndomethacin has a real or putative therapeutic role towards Hepatitis C, ChronicixnIndomethacin inhibits the reaction [interferon alfa-n1 results in increased secretion of IL4 protein]ixninterferon alfa-n1 has a real or putative therapeutic role towards Hepatitis C, Chronicixninterferon alfa-n1 results in increased secretion of IL4 proteinixnIndomethacin inhibits the reaction [interferon alfa-n1 results in increased secretion of IL10 protein]ixninterferon alfa-n1 results in increased secretion of IL2 proteinixninterferon alfa-n1 results in increased secretion of IL10 proteinixnIndomethacin promotes the reaction [interferon alfa-n1 results in increased secretion of IL2 protein]ixnIndomethacin results in decreased secretion of IL4 proteinixnIndomethacin results in decreased secretion of IL10 protein16478754title0Selective increases in the cytokine, TNFalpha, in the prefrontal cortex of PCP-treated rats and human schizophrenic subjects: influence of antipsychotic drugs.abstract160The psychotomimetic drug phencyclidine (PCP) induces symptoms closely related to those of schizophrenia in humans. In order to test the hypothesis that cytokines may be involved in the aetiology and treatment of schizophrenia, this study investigated the levels of cytokine mRNAs in rat brain after acute and chronic administration of PCP, in the presence and absence of antipsychotic drugs. The levels of the mRNAs encoding TNF, IL-2, IL-6, TGF 1, 2, 3, IL-3 and GM-CSF were measured in the prefrontal cortex, cortex, hippocampus, ventral and dorsal striatum regions of male hooded Long Evans rats after acute drug administration. Antipsychotic drugs and PCP significantly reduced the levels of TNF in the prefrontal cortex compared to vehicle-treated animals, whilst other cytokines remained unchanged. In addition, significant reductions in the levels of TNF mRNA in the prefrontal cortex still occurred 24h after acute PCP administration. However, levels of TNF mRNA were restored to control values after chronic PCP treatment, whereas increased expression was detected in animals co-administered with haloperidol. Levels of TNF mRNA were also found to be significantly increased in the prefrontal cortex of schizophrenic subjects. The relationship between TNF levels and schizophrenia are discussed.chemPHENCYCLIDINEchemHALOPERIDOLdiseaseSCHIZOPHRENIAgeneTNFgeneTGFB3geneTGFB1geneTGFB2geneIL2geneIL6geneIL3geneCSF2action termreactionaction termexpressionixnTNF plays a role in or acts as a marker for SchizophreniaixnHaloperidol affects the reaction [Phencyclidine affects the expression of TNF mRNA]ixnPhencyclidine affects the expression of TNF mRNAixnPhencyclidine does not affect the expression of CSF2 mRNAixnPhencyclidine does not affect the expression of IL2 mRNAixnPhencyclidine does not affect the expression of IL6 mRNAixnPhencyclidine does not affect the expression of IL3 mRNAixnPhencyclidine does not affect the expression of TGFB1 mRNAixnPhencyclidine does not affect the expression of TGFB2 mRNAixnPhencyclidine does not affect the expression of TGFB3 mRNA15363994title0Atorvastatin enhances sildenafil-induced vasodilation through nitric oxide-mediated mechanisms.abstract96Statins have cholesterol-independent effects including an increased vascular nitric oxide (NO) activity and are commonly used by patients with cardiovascular disease. Such patients frequently have erectile dysfunction, which may be treated with sildenafil, a selective inhibitor of phosphodiesterase type 5. Since statins and sildenafil can activate the NO-cGMP pathway, we investigated whether pre-treatment with atorvastatin (0, 5 and 30 mg/kg/day) for 2 weeks affects sildenafil (1 pM-100 mM)-induced relaxation of aortic rings isolated from Wistar rats. We also examined the hemodynamic consequences of this interaction in Wistar rats. Plasma nitrite/nitrate (NOx) concentrations were determined using an ozone-based chemiluminescence assay. While pre-treatment with atorvastatin increased the potency of sildenafil-induced vasorelaxation (P<0.01), no differences were observed in the maximum sildenafil-induced relaxation. Pre-incubation of aortic rings with NG-nitro-L-arginine methyl ester (L-NAME) reversed atorvastatin-induced increase in the potency of sildenafil relaxation. In addition, pre-treatment with atorvastatin enhanced plasma NOx concentrations and sildenafil-induced hypotension and tachycardia (all P<0.05). These results suggest that atorvastatin increases the vascular sensitivity to sildenafil through NO-mediated mechanisms.chemHYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORSchemATORVASTATINchemSILDENAFILdiseaseHYPOTENSIONdiseaseTACHYCARDIAdiseaseERECTILE DYSFUNCTIONgenePDE5Aaction termactivityixnsildenafil plays a role in or acts as a marker for Hypotensionixnsildenafil results in decreased activity of PDE5A proteinixnHydroxymethylglutaryl-CoA Reductase Inhibitors plays a role in or acts as a marker for Erectile Dysfunctionixnsildenafil has a real or putative therapeutic role towards Erectile Dysfunctionixnatorvastatin plays a role in or acts as a marker for Hypotensionixnatorvastatin plays a role in or acts as a marker for Tachycardiaixnsildenafil plays a role in or acts as a marker for Tachycardia12145768title0Upregulation of vasopressin V2 and aquaporin 2 in the inner medullary collecting duct of cardiomyopathic hamsters is attenuated by enalapril treatment.abstract152Previous studies showed that aquaporin 2 (AQP2) is elevated in the kidney of the heart failure rat suggesting that an increased amount of AQP2 contributes to water retention in heart failure. We performed the present study to determine whether angiotensin II play a role in causing an increase in the expression of arginine vasopressin (AVP) V2 and AQP2 mRNA in the kidney of the cardiomyopathic hamster. The expression of AVP V2 and AQP2 mRNA in the inner medullary collecting duct (IMCD) was measured by competitive reverse transcriptase-polymerase chain reaction (RT-PCR) before and after treatment with an angiotensin-converting enzyme inhibitor, enalapril. Our results showed that the expression of AVP V2 (0.53 +/- 0.05 v 1.03 +/- 0.15 amol/microg of total RNA, P <.01) and AQP2 mRNA (0.027 +/- 0.002 v 0.036 +/- 0.002 amol/microg of total RNA, P <.05) in the IMCD of the cardiomyopathic hamster is upregulated. Treating the cardiomyopathic hamster with enalapril for 7 days negated the changes. In situ hybridization experiments confirmed the intensity of the signals for both AVP V2 and AQP2 mRNA was more intense in the IMCD of the cardiomyopathic hamster. Enalapril treatment reduced the signal intensity to a level comparable to the normal hamster. These results suggested that the increases in the expression of AVP V2 and AQP2 mRNA are mediated by angiotensin II.chemENALAPRILdiseaseHEART FAILUREdiseaseCARDIOMYOPATHIESgeneAGTgeneAVPgeneAVPR2geneAQP2action termexpressionixnAVPR2 plays a role in or acts as a marker for Heart FailureixnEnalapril results in decreased expression of AVP proteinixnAVP plays a role in or acts as a marker for CardiomyopathiesixnAQP2 plays a role in or acts as a marker for CardiomyopathiesixnEnalapril results in decreased expression of AGT protein modified formixnEnalapril results in decreased expression of AQP2 mRNAixnAVPR2 plays a role in or acts as a marker for CardiomyopathiesixnAGT plays a role in or acts as a marker for CardiomyopathiesixnEnalapril results in decreased expression of AVPR2 mRNA10596698title0Effects of theophylline, dexamethasone and salbutamol on cytokine gene expression in human peripheral blood CD4+ T-cells.abstract122CD4+ T-cells are considered as pivotal in orchestrating the airway inflammation in asthma through the actions of their cytokines. Current hypothesis suggests that the anti-asthma effect of theophylline may be due to its anti-inflammatory actions, although the exact mechanisms remain unclear. The in vitro effect of theophylline on cytokine gene expression in peripheral blood CD4+ T-cells in normal subjects was compared with that of dexamethasone and salbutamol. CD4+ T-cells were cultured with phytohaemagglutin and phorbol myristate acetate in the presence of different concentrations of theophylline (10(-8)-10(-3) M or 0.0018-180 microg x mL(-1)) in one group of subjects (n=8), dexamethasone (10(-9)-10(-6) M or 0.39-390 ng x mL(-1)) in a second group (n=8) and salbutamol (10(-9)-10(-4) M or 0.00058-58 microg x mL(-1)) in a third group (n=8). Gene expression of interleukin (IL)-3, IL-4, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)-gamma was semiquantified by reverse transcription-polymerase chain reaction. Suppressed expression of IL-3 (36.9%), IL4 (38.8%), GM-CSF (24.6%) and IFN-gamma (37.7%), but not of IL-5, was only seen with theophylline at a concentration of 10(-3) M (180 microg x mL(-1)) (p<0.05) and not at lower concentrations. In contrast, dexamethasone caused a dose-dependent suppression of transcription of all cytokines, with 39.5% for IL-3, 84.4% for IL-4, 40.6% for IL-5, 50.9% for GM-CSF and 31.8% for IFN-gamma at 10(-6) M (390 ng x mL(-1)) (p<0.05-0.001). Salbutamol did not suppress gene expression of any o